Phenyl-[4-(3-phenyl-1h-pyrazol-4-yl)-pyrimidin-2-yl)-amine derivatives

ABSTRACT

The invention relates to phenyl-[4-(3-phenyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine derivatives and to processes for the preparation thereof, to pharmaceutical compositions comprising such derivatives and to the use of such derivatives—alone or in combination with one or more other pharmaceutically active compounds—for the preparation of pharmaceutical compositions for the treatment especially of a proliferative disease, such as a tumor.

This application is a 371 of PCT/EP03/07350 filed Jul. 8, 2003.

The invention relates tophenyl-[4-(3-phenyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine derivativesand to processes for the preparation thereof, to pharmaceuticalcompositions comprising such derivatives and to the use of suchderivatives—alone or in combination with one or more otherpharmaceutically active compounds—for the preparation of pharmaceuticalcompositions for the treatment especially of a proliferative disease,such as a tumour.

The invention relates tophenyl-[4-(3-phenyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine derivativesof formula I

wherein

m is from 1 to 5;

R₁ is lower alkyl-sulfonyl; unsubstituted, mono- or di-substitutedamino-sulfonyl; unsubstituted, mono- or di-substituted amino; aheterocyclic radical; lower alkyl substituted by a heterocyclic radicalor by heterocyclyl-NH— or heterocyclyl-O— wherein heterocyclyl is boundto NH or O via a carbon ring atom; a radical R₄-lower alkyl-X—, whereinR₄ is hydrogen, halogen, unsubstituted, mono- or di-substituted amino,or a heterocyclic radical, and X is —S— or —O—; or a radical R₅—C(═O)—,wherein R₅ is hydrogen, unsubstituted or substituted lower alkyl, freeor etherified hydroxy, unsubstituted, mono- or di-substituted amino, ora heterocyclic radical; wherein the R₁ substituents are selectedindependently of one another if m>1;

or two vicinal R₁ substituents together with the phenyl carbon atoms towhich they are attached form a heterocyclic ring;

R₂ is hydrogen, unsubstituted or substituted lower alkyl or aheterocyclic radical;

R₃ is hydrogen or a radical of the formula Ia

wherein n is from 0 to 5; and

Z is halogen; unsubstituted or substituted lower alkyl; or free,etherified or esterified hydroxy; wherein the Z substituents areselected independently of one another if n>1; or two vicinal Zsubstituents together with the phenyl carbon atoms to which they areattached form a heterocyclic ring; and

R₃′ is hydrogen if R₃ is a radical of the formula Ia or R₃′ is a radicalof the formula Ia as defined for R₃ if R₃ is hydrogen;

with the proviso that R₁ is not methoxy if m and n are both 1, R₂ ishydrogen and Z is fluoro;

or a salt of the said compounds.

The general terms used hereinbefore and hereinafter preferably havewithin the context of this disclosure the following meanings, unlessotherwise indicated:

Where the plural form is used for compounds, salts, and the like, thisis taken to mean also a single compound, salt, or the like.

Asymmetric carbon atoms of a compound of formula I that are optionallypresent may exist in the (R), (S) or (R,S) configuration, preferably inthe (R) or (S) configuration. Substituents at a double bond or a ringmay be present in cis- (=Z-) or trans (=E-) form. The compounds may thusbe present as mixtures of isomers or preferably as pure isomers.

Preferably alkyl contains up to 20 carbon atoms and is most preferablylower alkyl.

The prefix “lower” denotes a radical having up to and including amaximum of 7, especially up to and including a maximum of 4 carbonatoms, the radicals in question being either unbranched or branched withsingle or multiple branching.

Lower alkyl is, for example, methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl,neopentyl, n-hexyl or n-heptyl.

Lower alkyl R₂ is preferably methyl, ethyl or isopropyl, most preferablymethyl.

Lower alkyl Z is preferably methyl or ethyl.

Substituted lower alkyl is lower alkyl as defined above where one ormore substituents may be present, such as amino, N-lower alkylamino,N,N-di-lower alkylamino, N-lower alkanoylamino, N,N-di-loweralkanoylamino, hydroxy, lower alkoxy, lower alkanoyl, lower alkanoyloxy,cyano, nitro, carboxy, lower alkoxycarbonyl, carbamoyl, amidino,guanidino, ureido, mercapto, lower alkylthio, halogen or a heterocyclicradical.

Substituted lower alkyl R₂ is preferably lower alkyl substituted byN,N-di-lower alkylamino or lower alkyl-piperidyl.

Substituted lower alkyl Z is preferably lower alkyl substituted byhalogen such as especially trifluoromethyl.

Mono- or di-substituted amino-sulfonyl is amino-sulfonyl, wherein theamino group is substituted by one or two radicals selected independentlyof one another from e.g. unsubstituted or substituted lower alkyl or aheterocyclic radical.

Unsubstituted, mono- or di-substituted amino-sulfonyl R₁ is preferablyunsubstituted amino-sulfonyl.

Mono- or di-substituted amino is amino substituted by one or tworadicals selected independently of one another from e.g. unsubstitutedor substituted lower alkyl or a heterocyclic radical.

Mono- or di-substituted amino R₁ is preferably N-lower alkylamino orN,N-di-lower alkylamino, respectively.

Mono- or di-substituted amino R₄ is preferably N-lower alkylamino orN,N-di-lower alkylamino, respectively.

R₄-lower alkyl-X—, wherein R₄ is halogen, includes that the lower alkylmoiety of R₄-lower alkyl-X— is substituted with more than one halogenatom, i.e. with up to three halogen atoms, and is preferablytrifluoro-lower-alkyl-X.

A heterocyclic radical contains especially up to 20 carbon atomsincluding possible substituents and is an unsaturated, partiallyunsaturated, or preferably saturated monocyclic radical having from 4 or8 ring members and from 1 to 4, especially from 1 to 3, and mostpreferably 1 or 2 heteroatoms which are preferably selected fromnitrogen, oxygen and sulfur, or a bi- or tricyclic radical wherein, forexample, one or two benzene radicals are annellated (fused) to thementioned monocyclic radical. The heterocyclic radical is optionallysubstituted by one or more radicals such as e.g. unsubstituted orsubstituted lower alkyl.

In heterocyclyl-NH— and heterocyclyl-O—, the heterocyclyl moiety is asdefined for a heterocyclic radical in the preceding paragraph with theproviso that it is bound to NH and O, respectively, via a carbon ringatom and is preferably piperidyl substituted by lower alkyl, such asespecially 2,2,6,6-tetramethyl-piperidin-4-yl or1-methyl-piperidin-4-yl.

A heterocyclic radical R₁ is preferably lower alkyl-piperazinyl,especially 4-lower alkyl-piperazin-1-yl.

The heterocyclic ring formed by two vicinal R₁ substituents togetherwith the phenyl carbon atoms to which they are attached containsespecially up to 20 carbon atoms including possible substituents and isan unsaturated, partially unsaturated, or saturated monocyclic radicalhaving from 4 or 8 ring members and from 1 to 3 heteroatoms which arepreferably selected from nitrogen, oxygen and sulfur. The heterocyclicring is optionally substituted by one or more radicals such as e.g. oxo(═O), thioxo (═S), or unsubstituted or substituted lower alkyl.Preferably this ring is a thiazol, 1-oxo-thiazol or dioxol ring.

Lower alkyl substituted by a heterocyclic radical R₁ is preferably loweralkyl substituted by lower alkyl-piperazinyl, especially by 4-loweralkyl-piperazin-1-yl.

A heterocyclic radical R₄ is preferably morpholin-4-yl, especiallymorpholin-4-yl, or lower alkyl-piperidyl, especially 1-loweralkyl-piperidin-4-yl.

A heterocyclic radical R₅ is preferably lower alkyl-piperazinyl,especially 4-lower alkyl-piperazin-1-yl.

A heterocyclic radical R₂ is preferably bound to the rest of themolecule of formula I via a carbon ring atom and is especiallypiperidyl, such as piperidin-4-yl, lower alkyl-piperidyl, such as1-lower alkyl-piperidin-4-yl, or tetrahydro-pyranyl, such astetrahydro-pyran-4-yl.

Etherified hydroxy is, for example, alkoxy, especially lower alkoxy,such as methoxy, ethoxy and tert-butoxy.

Etherified hydroxy R₅ is preferably lower alkoxy, especially ethoxy ortert-butoxy.

Etherified hydroxy Z is preferably lower alkoxy, especially methoxy orethoxy, or phenyl-lower alkoxy, wherein the phenyl moiety is preferablyunsubstituted or substituted by e.g. unsubstituted or substituted loweralkyl.

Esterified hydroxy is preferably hydroxy esterified by an organiccarboxylic acid, such as alkanoic acid, and is for example loweralkanoyloxy.

Halogen is primarily fluorine, chlorine, bromine, or iodine, especiallyfluorine, chlorine, or bromine.

Halogen Z is preferably chloro.

X is preferably —O—.

m is preferably from 1 to 3.

n is preferably 1 or 2.

R₁ is preferably attached to the phenyl ring in the meta and/or paraposition.

Z is preferably attached to the phenyl ring in the meta and/or paraposition.

R₄ is preferably mono- or di-substituted amino, or a heterocylicradical.

Salts are especially the pharmaceutically acceptable salts of compoundsof formula I.

Such salts are formed, for example, as acid addition salts, preferablywith organic or inorganic acids, from compounds of formula I with abasic nitrogen atom, especially the pharmaceutically acceptable salts.

In the presence of negatively charged radicals, such as carboxy orsulfo, salts may also be formed with bases, e.g. metal or ammoniumsalts, such as alkali metal or alkaline earth metal salts, or ammoniumsalts with ammonia or suitable organic amines, such as tertiarymonoamines.

In the presence of a basic group and an acid group in the same molecule,a compound of formula I may also form internal salts.

For isolation or purification purposes it is also possible to usepharmaceutically unacceptable salts, for example picrates orperchlorates. Only the pharmaceutically acceptable salts or freecompounds (if the occasion arises, in the form of pharmaceuticalcompositions) attain therapeutic use, and these are therefore preferred.

In view of the close relationship between the novel compounds in freeform and in the form of their salts, including those salts that can beused as intermediates, for example in the purification or identificationof the novel compounds, hereinbefore and hereinafter any reference tothe free compounds is to be understood as referring also to thecorresponding salts, as appropriate and expedient.

The compounds of formula I have valuable, pharmacologically usefulproperties. In particular they are useful for the treatment ofproliferative disorders such as especially solid cancers like forexample non-small cell lung cancer, squameous carcinoma (head and neck),breast, gastric, ovarian, colon and prostate cancers and gliomas, aswell as leukemias, such as especially acute myeloid leukemia (AML) andchronic myeloid leukemia (CML).

The compounds of formula I are effective especially as protein tyrosinekinase inhibitors and/or (furthermore) as inhibitors of serine/threonineprotein kinases; they exhibit, for example, powerful inhibition of thetyrosine kinase activity of the epidermal growth factor receptor (EGF-R)and of ErbB-2 kinase. These two protein tyrosine kinase receptors,together with their family members ErbB-3 and ErbB-4, play a key role insignal transmission in a large number of mammalian cells, includinghuman cells, especially epithelial cells, cells of the immune system andcells of the central and peripheral nervous system. For example, invarious cell types, EGF-induced activation of receptor-associatedprotein tyrosine kinase is a prerequisite for cell division and hencefor the proliferation of the cell population. Most importantly,overexpression of the EGF-R (HER-1) and/or ErbB2 (HER-2) has beenobserved in substantial fractions of many human tumours. EGF-R, e.g.,was found to be overexpressed in non-small cell lung cancers, squameouscarcinoma (head and neck), breast, gastric, ovarian, colon and prostatecancers as well as in gliomas. ErbB2 was found to be overexpressed insquameous carcinoma (head and neck), breast, gastric, and ovariancancers as well as in gliomas.

In addition to inhibiting the tyrosine kinase activity of the EGF-R, thecompounds of formula I also inhibit to varying extents other proteintyrosine kinases that are involved in signal transmission mediated bytrophic factors, specially the vascular endothelial growth factor (VEGF)receptor family (e.g. KDR, Flt-1) but also abl kinase, especially v-abl,Flt-3, kinases from the family of Src, especially c-Src, Lck and Fyn,the other members of the EGF receptor family such as ErbB3 (HER-3) andErbB4 (HER4), CSF-1 receptor, c-Kit, FGF receptor and thecyclin-dependent kinases CDK1 and CDK2, all of which play a part ingrowth regulation and transformation in mammalian cells, including humancells.

The inhibition of EGF-R tyrosine kinase activity can be demonstratedusing known methods, for example using the recombinant intracellulardomain of the EGF-receptor [EGF-R ICD; see, for example, E. McGlynn etal., Europ. J. Biochem. 207, 265-275 (1992)]. Compared with the controlwithout inhibitor, the compounds of formula I inhibit the enzymeactivity by 50% (IC₅₀), for example in a concentration of from 0.0005 to0.5 μM, especially from 0.001 to 0.1 μM.

As well as or instead of inhibiting EGF-R tyrosine kinase activity, thecompounds of formula I also inhibit other members of this family ofreceptors, like ErbB2. The inhibitory activity (IC₅₀) is approximatelyin the range of 0.001 to 0.5 μM. The inhibition of ErbB2 tyrosine kinase(HER-2) can be determined, for example, analogously to the method usedfor EGF-R protein tyrosine kinase [see C. House et al., Europ. J.Biochem. 140. 363-367 (1984)]. The ErbB-2 kinase can be isolated, andits activity determined, by means of protocols known per se, for examplein accordance with T. Akiyama et al., Science 232 1644 (1986).

Surprisingly, the compounds of formula I especially also inhibit thetyrosine kinase activity of the VEGF receptor family very potently. Thecompounds of the present invention are therefore very effective dualinhibitors of EGF- and VEGF-receptor family members. For inhibition ofKDR and Flt-1 and inhibition of growth factor-induced proliferation ofHUVECS see J. Wood et al., Cancer Res. 60, 2178-2189 (2000). Thecompounds of formula I inhibit e.g. the KDR tyrosine kinase activitywith an IC₅₀ of from about 1 nM to about 1 μM, especially from about 5nM to about 0.5 μM.

The action of the compounds of formula I on EGF-induced phosphorylationof the EGF-R can be determined in the human A431 epithelial carcinomacell line by means of an ELISA which is described in U. Trinks et al.,J. Med. Chem. 37:7, 1015-1027 (1994). In that test (EGF-R ELISA) thecompounds of formula I exhibit an IC₅₀ of approximately from 0.001 to 1μM.

The compounds of formula I potently inhibit the growth of EGF-Roverexpressing NCl-H596 non-small cell lung carcinoma cells [see e.g. W.Lei, et al., Anticancer Res. 19(1A), 221-228 (1999)]at an IC₅₀ ofapproximately 0.01 to 1 μM. In the same range of activity, the compoundsof formula I also potently inhibit the growth of ErbB-2-overexpressingBT474 human breast cancer cells. The test procedures are adapted from T.Meyer et al., Int. J. Cancer 43, 851 (1989). The inhibitory activity ofthe compounds of formula I is determined, briefly, as follows: NCl-H596cells (10 000/microtitre plate well) are transferred to 96-wellmicrotitre plates. The test compounds [dissolved in dimethyl sulfoxide(DMSO)] are added in a series of concentrations (dilution series) insuch a manner that the final concentration of DMSO is not greater than1% (v/v). After the addition, the plates are incubated for three daysduring which the control cultures without test compound are able toundergo at least three cell-division cycles. The growth of the NCl-H596cells is measured by means of methylene blue staining: after theincubation the cells are fixed with glutaraldehyde, washed with waterand stained with 0.05% methylene blue. After a washing step the stain iseluted with 3% HCl and the optical density (OD) per well of themicrotitre plate is measured using a Titertek Multiskan (Titertek,Huntsville, Ala., USA) at 665 nm. IC₅₀ values are determined by acomputer-aided system using the formula:IC₅₀=[(OD_(test)−OD_(start))/(OD_(control)−OD_(start))]×100.

The IC₅₀ value in those experiments is given as that concentration ofthe test compound in question that results in a cell count that is 50%lower than that obtained using the control without inhibitor. Thecompounds of formula I exhibit inhibitory activity with an IC₅₀ in therange from approximately 0.01 to 1 μM.

The compounds of formula I exhibit inhibition of the growth of tumourcells also in vivo, as shown, for example, by the test described below:the test is based on inhibition of the growth of the human squamous lungcarcinoma cell line NCl-H596 [ATCC HTB 178; American Type CultureCollection, Rockville, Md., USA; see Santon, J. B., et al., CancerResearch 46, 4701-4705 (1986) and Ozawa, S., et al., Int. J. Cancer 40,706-710 (1987)], which is transplanted into female BALB/c nude mice(Bomholtgard, Denmark). That carcinoma exhibits a growth that correlateswith the extent of the expression of the EGF-R. Tumours are establishedafter subcutaneous (s.c.) injection of cells [a minimum of 2×10⁶ cellsin 100 μl phosphate-buffered saline (PBS) or medium] in carrier mice(4-8 mice). Injections are made s.c. in the left flank of the mousemid-way between the tail and the head. The resulting tumours areserially passaged for a minimum of three consecutive transplantationsprior to start of the treatment. During this time tumour growth ratesstabilize. Tumours are not passaged more than 12 times. For the therapyexperiment tumour fragments of roughly 25 mg are transplanted s.c. intothe left flank of the animals using a 13-gauge trocar needle underForene® (Abbott, Schwitzerland) anesthesia. Tumour growth and bodyweights are monitored twice per week. All treatments are initiated whenthe tumour attains a volume of 100 to 250 mm³. The tumour volumes arecalculated using the known formula Length×Diameter²×π/6 [see Evans, B.D., et al., Brit. J. Cancer 45, 466-8 (1982)]. Antitumour activity isexpressed as T/C % (mean increase of tumour volumes of treated animalsdivided by the mean increase of tumour volumes of control animalsmultiplied by 100%). At a dose of from 3 to 100 mg/kg of activeingredient, distinct inhibition of the tumour growth is found, forexample T/C % values of less than 50.

The compounds of formula I may inhibit other protein tyrosine kinasesthat are involved in signal transmission mediated by trophic factors,for example abl kinase, such as especially v-abl kinase (IC₅₀ forexample from 0.01 to 5 μM), kinases from the family of the src kinases,such as especially c-src kinase (IC₅₀ for example from 0.1 to 10 μM) andserine/threonine kinases, for example protein kinase C, especiallyA-Raf, B-Raf and c-Raf and subfamilies thereof, all of these kinasesbeing involved in growth regulation and transformation in mammaliancells, including human cells.

The above-mentioned inhibition of v-abl tyrosine kinase is determined bythe methods of N. Lydon et al., Oncogene Research 5, 161-173 (1990) andJ. F. Geissler et al., Cancer Research 52, 4492-4498 (1992). In thosemethods [Val⁵]-angiotensin II and [β-³²P]-ATP are used as substrates.

The compounds of formula I which inhibit the tyrosine kinase activity ofthe EGF-R or of the other protein tyrosine kinases mentioned aretherefore useful, for example, in the treatment of benign or malignanttumours. The compounds of formula I are e.g. able to simultaneouslyinhibit the growth of tumours with deregulated EGF-R and/or ErbB-2activity as well as to inhibit the vascularisation of solid tumourstriggered by VEGF. This combined activity leads to an improvedantitumour effect (see also WO 02/41882). Moreover, the use of a dualinhibitor reduces the risk of drug-drug interactions and further reducesthe total drug load as compared to a combination therapy. The compoundsof formula I are capable of slowing down tumour growth or effectingtumour regression and of preventing the formation of tumour metastasesand the growth of micrometastases. They can be used especially in thecase of epidermal hyperproliferation (psoriasis), in the treatment ofsolid cancers like for example non-small cell lung cancer, squameouscarcinoma (head and neck), breast, gastric, ovarian, colon and prostatecancers as well as gliomas and in the treatment of leukemias, such asespecially acute myeloid leukemia (AML) and chronic myeloid leukemia(CML). In addition, the compounds of formula I can be used in thetreatment of those disorders of the immune system in which several or,especially, individual protein tyrosine kinases and/or (furthermore)serine/threonine protein kinases are involved; the compounds of formulaI can also be used in the treatment of those disorders of the central orperipheral nervous system in which signal transmission by several or,especially, a single protein tyrosine kinase(s) and/or (furthermore)serine/threonine protein kinase(s) is/are involved.

In general, the present invention relates also to the use of thecompounds of formula I for the inhibition of the mentioned proteinkinases, in particular to their use for the dual inhibition of EGF- andVEGF-receptor family members.

The compounds according to the invention can be used both alone and incombination with other pharmacologically active compounds, for exampletogether with inhibitors of the enzymes of polyamine synthesis,inhibitors of protein kinase C, inhibitors of other tyrosine kinases,cytokines, negative growth regulators, for example TGF-β or IFN-β,aromatase inhibitors, antioestrogens and/or cytostatic drugs.

With the groups of preferred compounds of formula I mentionedhereinafter, definitions of substituents from the general definitionsmentioned hereinbefore may reasonably be used, for example, to replacemore general definitions with more specific definitions or especiallywith definitions characterized as being preferred.

Preference is given to a compound of formula I, wherein

m is an integer from 1 to 5;

R₁ is unsubstituted, mono- or di-substituted amino-sulfonyl;unsubstituted, mono- or di-substituted amino; a heterocylic radical;lower alkyl substituted by a heterocyclic radical; a radical R₄loweralkyl-X—, wherein R₄ is hydrogen, unsubstituted, mono- or di-substitutedamino, or a heterocyclic radical, and X is —S— or —O—; or a radicalR₅—C(═O)—, wherein R₅ is hydrogen, unsubstituted or substituted loweralkyl, free or etherified hydroxy, unsubstituted, mono- ordi-substituted amino, or a heterocyclic radical; wherein the R₁substituents are selected independently of one another if m>1;

or two vicinal R₁ substituents together with the phenyl carbon atoms towhich they are attached form a heterocylic ring;

R₂ is hydrogen, unsubstituted or substituted lower alkyl or aheterocyclic radical;

R₃ is a radical of the formula Ia, wherein n is from 1 to 5 and Z ishalogen; unsubstituted or substituted lower alkyl; or free, etherifiedor esterified hydroxy; wherein the Z substituents are selectedindependently of one another if n>1;

or two vicinal Z substituents together with the phenyl carbon atoms towhich they are attached form a heterocyclic ring; and

R₃′ is hydrogen;

with the proviso that R₁ is not methoxy if m and n are both 1, R₂ ishydrogen and Z is fluoro;

and the salts thereof.

Preference is further also given to a compound of formula I, wherein

m is an integer from 1 to 5;

R₁ is unsubstituted, mono- or di-substituted amino-sulfonyl;unsubstituted, mono- or di-substituted amino; a heterocyclic radical;lower alkyl substituted by a heterocyclic radical; a radical R₄-loweralkyl-X—, wherein R₄ is hydrogen, unsubstituted, mono- or di-substitutedamino, or a heterocyclic radical, and X is —S— or —O—; or a radicalR₅—C(═O)—, wherein R₅ is hydrogen, unsubstituted or substituted loweralkyl, free or etherified hydroxy, unsubstituted, mono- ordi-substituted amino, or a heterocyclic radical; wherein the R₁substituents are selected independently of one another if m>1;

or two vicinal R₁ substituents together with the phenyl carbon atoms towhich they are attached form a heterocyclic ring;

R₂ is hydrogen;

R₃ is a radical of the formula Ia, wherein n is from 1 to 5 and Z ishalogen; unsubstituted or substituted lower alkyl; or free, etherifiedor esterified hydroxy; wherein the Z substituents are selectedindependently of one another if n>1;

or two vicinal Z substituents together with the phenyl carbon atoms towhich they are attached form a heterocyclic ring; and

R₃′ is hydrogen;

with the proviso that R₁ is not methoxy if m and n are both 1, R₂ ishydrogen and Z is fluoro;

and the salts thereof.

Special preference is given to a compound of formula I, wherein

m is an integer from 1 to 3;

R₁ is amino-sulfonyl; mono- or di-substituted amino; a heterocyclicradical; lower alkyl substituted by a heterocyclic radical; a radical R₄lower alkyl-X—, wherein R₄ is hydrogen, mono- or di-substituted amino,or a heterocyclic radical, and X is —S— or —O—; or a radical R₅—C(═O)—,wherein R₅ is lower alkyl, free or etherified hydroxy, or a heterocyclicradical;

wherein the R₁ substituents are selected independently of one another ifm>1;

or two vicinal R₁ substituents together with the phenyl carbon atoms towhich they are attached form a heterocyclic ring;

R₂ is hydrogen;

R₃ is a radical of the formula Ia, wherein n is from 1 to 3 and Z ishalogen; lower alkyl; or free or etherified hydroxy; wherein the Zsubstituents are selected independently of one another if n>1;

or two vicinal Z substituents together with the phenyl carbon atoms towhich they are attached form a heterocyclic ring; and

R₃′ is hydrogen;

with the proviso that R₁ is not methoxy if m and n are both 1, R₂ ishydrogen and Z is fluoro;

and the salts thereof.

Very special preference is given to a compound of formula I, wherein

m is an integer from 1 to 3;

R₁ is lower alkyl-sulfonyl; amino-sulfonyl; N,N-di-lower alkylamino;piperazinyl; lower alkyl-piperazinyl; tetrazolyl; lower alkylsubstituted by lower alkyl-piperazinyl, hydroxy-lower alkyl-piperazinyl,piperidyl-amino or piperidyl-oxy wherein the piperidyl moiety issubstituted by 1 to 4 lower alkyl radicals; a radical R₄-lower alkyl-X—,wherein R₄ is hydrogen, halogen, N,N-di-lower alkylamino, morpholinyl orlower alkyl-piperidyl, and X is —S— or —O—; or a radical R₅—C(═O)—,wherein R₅ is lower alkyl, hydroxy, lower alkoxy or loweralkyl-piperazinyl; wherein the R₁ substituents are selectedindependently of one another if m>1;

or two vicinal R₁ substituents together with the phenyl carbon atoms towhich they are attached form a thiazol or 1-oxo-thiazol ring;

R₂ is hydrogen lower alkyl, N,N-di-lower alkylamino-lower alkyl, loweralkyl-piperidyl or lower alkyl-piperidyl-lower alkyl;

R₃ is a radical of the formula Ia, wherein n is 0, 1 or 2 and Z ishalogen, lower alkyl, tri-halogen-lower alkyl, hydroxy, lower alkoxy orphenyl-lower alkoxy; wherein the Z substituents are selectedindependently of one another if n is 2;

or two Z radicals together form a dioxol ring; and

R₃′ is hydrogen;

with the proviso that R₁ is not methoxy if m and n are both 1, R₂ ishydrogen and Z is fluoro;

and the salts thereof.

Very special preference is further given to a compound of formula I,wherein

m is an integer from 1 to 3;

R₁ is amino-sulfonyl; N,N-di-lower alkylamino; lower alkyl-piperazinyl;lower alkyl substituted by lower alkyl-piperazinyl; a radical R₄-loweralkyl-X—, wherein R₄ is hydrogen, N,N-di-lower alkylamino, morpholinylor lower alkyl-piperidyl, and X is —S— or —O—; or a radical R₅—C(═O)—,wherein R₅ is lower alkyl, hydroxy, lower alkoxy or loweralkyl-piperazinyl; wherein the R₁ substituents are selectedindependently of one another if m>1;

or two vicinal R₁ substituents together with the phenyl carbon atoms towhich they are attached form a thiazol or 1-oxo-thiazol ring;

R₂ is hydrogen;

R₃ is a radical of the formula Ia, wherein n is 1 or 2 and Z is halogen,lower alkyl, hydroxy, lower alkoxy or phenyl-lower alkoxy; wherein the Zsubstituents are selected independently of one another if n is 2;

or two Z radicals together form a dioxol ring; and

R₃′ is hydrogen;

with the proviso that R₁ is not methoxy if m and n are both 1, R₂ ishydrogen and Z is fluoro;

and the salts thereof.

Very special preference is also given to a compound of formula I,wherein m, R₁, R₂, R₃ and R₃′ have the meanings as defined for acompound of formula I, especially as defined for the preferred compoundsof formula I, with the proviso that R₁ is not a radical R₄-loweralkyl-X—, and to salts of such compounds.

Very special preference is further given to a compound of formula I,wherein

m is 1 or 2;

R₁ is amino-sulfonyl; N,N-di-lower alkylamino; lower alkyl-piperazinyl;lower alkyl substituted by lower alkyl-piperazinyl; or a radicalR₅—C(═O)—, wherein R₅ is lower alkyl, hydroxy, lower alkoxy or loweralkyl-piperazinyl; wherein the R₁ substituents are selectedindependently of one another if m is 2;

or two vicinal R₁ substituents together with the phenyl carbon atoms towhich they are attached form a thiazol or 1-oxo-thiazol ring;

R₂ is hydrogen;

R₃ is a radical of the formula Ia, wherein n is 1 or 2 and Z is halogen,lower alkyl, hydroxy, or lower alkoxy; wherein the Z substituents areselected independently of one another if n is 2; and

R₃′ is hydrogen;

and the salts thereof.

Very special preference is also given to a compound of formula I,wherein R₁ is a heterocyclic radical or lower alkyl substituted by aheterocyclic radical, and the salts thereof.

Very special preference is further also given to a compound of formulaI, wherein (R₁)_(m), R₂, R₃ and R₃′ are selected independently of oneanother from the different meanings given for these substituents in theExamples below, or a salt, especially a pharmaceutically acceptablesalt, of such a compound.

Most special preference is given to a compound of formula I mentioned inthe Examples below, or a salt, especially a pharmaceutically acceptablesalt, thereof.

Also especially preferred are compounds of formula I, which—according tothe above-described tyrosine kinase inhibition assays—inhibit HER-1,HER-2 and KDR with IC₅₀ values of less than 300 nM, most preferably ofless than 100 nM.

Very special preference is further given to compounds of formula I whichinhibit the tyrosine kinase activity of at least one member of the EGFreceptor family together with at least one member of the VEGF receptorfamily (dual inhibition of EGF- and VEGF-receptor family members) withIC₅₀ values In the range of 0.5 nM to 0.5 μM, especially in the range of1 nM to 300 nM, based on the above-described tyrosine kinase inhibitionassays.

The compounds of formula I or salts thereof are prepared in accordancewith processes known per se, though not previously described for themanufacture of the compounds of the formula I, especially whereby

a) a compound of formula II

wherein Y is a leaving group such as halogen, —(═O)—CH₃ or —S(O₂)—CH₃and R₂, R₃ and R₃′ have the meanings as defined for a compound offormula I, is reacted with a compound of formula III

wherein m and R₁ have the meanings as defined for a compound of formulaI;

b) in order to prepare a compound of formula I, wherein R₁ is a radicalR₅—C(═O)— in which R₅ is mono- or di-substituted amino or a heterocyclicradical that is bound to the carbonyl moiety via a nitrogen ring atom, acompound of formula IV

wherein R₂, R₃ and R₃′ have the meanings as defined for a compound offormula I, or a reactive carboxylic acid derivative thereof, is reactedwith a mono- or di-substituted amine or a heterocyclic radicalcontaining at least one nitrogen ring atom to which a hydrogen is bound,respectively; or

c) in order to prepare a compound of formula I, wherein R₂ isunsubstituted or substituted lower alkyl or a heterocyclic radical, acompound of formula I, wherein R₂ is hydrogen, is reacted with acompound of the formula R₂—OH, wherein R₂ is unsubstituted orsubstituted lower alkyl or a heterocyclic radical wherein thesubstituted lower alkyl or the heterocyclic radical is attached to thehydroxy group of R₂—OH via a carbon atom of the lower alkyl moiety orvia a carbon ring atom of the heterocyclic radical, respectively;

whereby functional groups which are present in the starting compounds ofprocesses a) to c) and are not intended to take part In the reaction,are present in protected form if necessary, and protecting groups thatare present are cleaved, whereby the said starting compounds may alsoexist in the form of salts provided that a salt-forming group is presentand a reaction in salt form is possible;

and, if so desired, a compound of formula I thus obtained is convertedinto another compound of formula I, a free compound of formula I isconverted into a salt, an obtained salt of a compound of formula I isconverted into the free compound or another salt, and/or a mixture ofisomeric compounds of formula I is separated into the individualisomers.

Description of the Process Variants:

Regarding Process a):

The reaction between a compound of formula II, wherein Y is halogen, anda compound of formula III preferably takes place in a suitable inertsolvent such as dioxane, in the presence of an acid such as HCl, atelevated temperature, preferably at around 100° C. In a compound offormula II wherein Y is halogen, halogen is preferably chloro or bromo,especially chloro.

The reaction between a compound of formula II, wherein Y is —S(O₂)—CH₃,and a compound of formula III preferably takes place under thoseconditions described for the analogous procedure in Klutchko et al.,Journal of Medicinal Chemistry, 1998, Vol. 41, No. 17, 3276-3292.

The reaction between a compound of formula II, wherein Y is —S(═O)—CH₃,and a compound of formula III preferably takes place in a suitable inertsolvent such as 1,4-dioxane or tetrahydrofuran, in the presence ofBF₃.Et₂O, at elevated temperature, preferably at around 100° C.

Regarding Process b):

Reaction b), that is, the formation of amide bonds, preferably takesplace under standard conditions for the formation of peptide bonds(condensation reaction). In a reactive carboxylic acid derivative of acompound of the formula IV, the carboxyl group is either functionalizedas activated ester (reactive form). The reactive carboxyl groups are,however, preferably synthesized in situ (for example making use ofreagents customary in peptide chemistry, e.g. for the preparation of1-hydroxybenzotriazole, succinimide- or N-hydroxysuccinimide esters, orin situ derivatisation with condensing agents, e.g. with carbodiimides,such as dicyclohexylcarbodiimide, with carbonylimidazole, withN-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate-N-oxide(HATU); with2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluroniumtetrafluoroborat(HBTU), with2-(pyridon-1-yl)-1,1,3,3-tetramethyluroniumtetrafluoroborate (TPTU); orbenzotriazol-1-yl-oxy-tris(dimethylamino)phosphoniumhexafluorophosphate(BOP), or similar reagents). The condensation reaction preferably takesplace in the presence of a condensing agent, especially BOP, in anaprotic polar solvent, preferably a N,N-di-(lower alkyl)-loweralkanoylamide, such as dimethylformamide, at preferred temperatures inthe range from 0 to 50° C., e.g. at room temperature.

Regarding Process c):

The reaction between a compound of formula I, wherein R₂ is hydrogen,and a compound of the formula R₂—OH preferably takes place under theMitsunobu reaction conditions such as those described in: Mitsunobu,Oyo; Synthesis 1981, p. 1-27.

Compounds of formula I can be transformed into different compounds offormula I. Such transformations include: reduction of a carbonyl groupto a methylene group as in Example 32; ether cleavage as in Example 39;oxidation of a sulfide to a sulfoxide as in Example 45; de-chlorinationas in Example 104; alkylation as in Example 117.

Additonal Process Steps:

In the additional process steps, carried out as desired, functionalgroups of the starting compounds which should not take part in thereaction may be present in unprotected form or may be protected forexample by one or more protecting groups. The protecting groups are thenwholly or partly removed according to one of the known methods.

Protecting groups, and the manner in which they are introduced andremoved are described, for example, in “Protective Groups in OrganicChemistry”, Plenum Press, London, N.Y. 1973, and in “Methoden derorganischen Chemie”, Houben-Weyl, 4th edition, Vol. 15/1,Georg-Thieme-Verlag, Stuttgart 1974 and in Theodora W. Greene,“Protective Groups in Organic Synthesis”, John Wiley & Sons, New York1981. A characteristic of protecting groups is that they can be removedreadily, i.e. without the occurrence of undesired secondary reactions,for example by solvolysis, reduction, photolysis or alternatively underphysiological conditions.

The end products of formula I may however also contain substituents thatcan also be used as protecting groups in starting materials for thepreparation of other end products of formula I. Thus, within the scopeof this text, only a readily removable group that is not a constituentof the particular desired end product of formula I is designated a“protecting group”, unless the context indicates otherwise.

General Process Conditions:

All process steps described here can be carried out under known reactionconditions, preferably under those specifically mentioned, in theabsence of or usually in the presence of solvents or diluents,preferably those that are Inert to the reagents used and able todissolve them, in the absence or presence of catalysts, condensingagents or neutralising agents, for example ion exchangers, typicallycation exchangers, for example in the H⁺ form, depending on the type ofreaction and/or reactants at reduced, normal, or elevated temperature,for example in the range from −100° C. to about 190° C., preferably fromabout −80° C. to about 150° C., for example at −80 to −60° C., at RT, at−20 to 40° C., at 0 to 100° C. or at the boiling point of the solventused, under atmospheric pressure or in a closed vessel, if need be underpressure, and/or in an inert, for example an argon or nitrogen,atmosphere.

The invention relates also to those embodiments of the process in whichone starts from a compound obtainable at any stage as an intermediateand carries out the missing steps, or breaks off the process at anystage, or forms a starting material under the reaction conditions, oruses said starting material in the form of a reactive derivative orsalt, or produces a compound obtainable by means of the processaccording to the invention under those process conditions, and furtherprocesses the said compound in situ. In the preferred embodiment, onestarts from those starting materials which lead to the compoundsdescribed hereinabove as preferred.

In the preferred embodiment, a compound of formula I is preparedaccording to the processes and process steps defined in the Examples.

The compounds of formula I, including their salts, are also obtainablein the form of hydrates, or their crystals can include for example thesolvent used for crystallisation (present as solvates).

Starting Materials:

New starting materials and/or intermediates, as well as processes forthe preparation thereof, are likewise the subject of this invention. Inthe preferred embodiment, such starting materials are used and reactionconditions so selected as to enable the preferred compounds to beobtained.

The starting materials used in the above described processes a) to c)are known, capable of being prepared according to known processes, orcommercially obtainable; in particular, they can be prepared usingprocesses as described In the Examples.

In the preparation of starting materials, existing functional groupswhich do not participate in the reaction should, if necessary, beprotected. Preferred protecting groups, their introduction and theirremoval are described above or in the Examples. In place of therespective starting materials and transients, salts thereof may also beused for the reaction, provided that salt-forming groups are present andthe reaction with a salt is also possible. Where the term startingmaterials is used hereinbefore and hereinafter, the salts thereof arealways included, insofar as reasonable and possible.

A compound of formula II, wherein Y is halogen, R₂ is hydrogen or loweralkyl, and R₃ and R₃′ have the meanings as defined for a compound offormula I, can be prepared for example by reacting a compound of formulaV

wherein R₆ is halogen and n and Z have the meanings as defined for acompound of formula I with hydrazine (H₂N—NH₂) or N-loweralkyl-hydrazine (lower alkyl-NH—NH₂), respectively, in a suitablesolvent, e.g. lower alcohols, such as ethanol, preferably at around roomtemperature.

A compound of the formula II, wherein Y is halogen, R₂ is unsubstitutedor substituted lower alkyl or a heterocyclic radical, and R₃ and R₃′have the meanings as defined for a compound of formula I, can beprepared for example by reacting a compound of formula II, wherein Y ishalogen, R₂ is hydrogen and R₃ and R₃′ have the meanings as defined fora compound of formula I, with a compound of the formula R₂—OH, whereinR₂ is unsubstituted or substituted lower alkyl or a heterocyclic radicalwherein the substituted lower alkyl or the heterocyclic radical isattached to the hydroxy group of R₂—OH via a carbon atom of the loweralkyl moiety or via a carbon ring atom of the heterocyclic radical,respectively, e.g. under the Mitsunobu reaction conditions such as thosedescribed in: Mitsunobu, Oyo; Synthesis 1981, p. 1-27.

A compound of formula II, wherein Y is —S(O₂)—CH₃ and R₂, R₃ and R₃′have the meanings as defined for a compound of formula I, can beprepared for example by reacting a compound of formula VI

wherein R₂, R₃ and R₃′ have the meanings as defined for a compound offormula I, with 3-chloroperoxybenzoic acid in CHCl₃, e.g. under thoseconditions described for the analogous procedure in Klutchko et al.,Journal of Medicinal Chemistry, 1998, Vol. 41, No. 17, 3276-3292.

A compound of formula II, wherein Y is —S(═O)—CH₃ and R₂, R₃ and R₃′have the meanings as defined for a compound of formula I, can beprepared for example by reacting a compound of formula VI with3-chloroperoxybenzoic acid under conditions such as those described inM. P. Zawistoski, Journal of Heterocyclic Chemistry, 1991, Volume 28, p.657-665.

A compound of formula IV, or a reactive carboxylic acid derivativethereof, wherein R₂, R₃ and R₃′ have the meanings as defined for acompound of formula I, can be prepared for example by reacting acompound of formula II, wherein Y is a leaving group such as halogen,—S(═O)—CH₃ or —S(O₂)—CH₃ and R₂, R₃ and R₃′ have the meanings as definedfor a compound of formula I, with amino-benzoic acid, e.g. underconditions described for the reaction of a compound of formula II with acompound of formula III, and activate the carboxy group of benzoic acidthereafter.

A compound of formula VI, wherein R₂ is hydrogen or lower alkyl and R₃and R₃′ have the meanings as defined for a compound of formula I, can beprepared for example by reacting a compound of formula V, wherein R₆ is—S—CH₃ and n and Z have the meanings as defined for a compound offormula I, with hydrazine (H₂N—NH₂) or N-lower alkyl-hydrazine (loweralkyl-NH—NH₂), respectively, in a suitable solvent, e.g. lower alcohols,such as ethanol, preferably at around room temperature.

A compound of formula VI, wherein R₂ is unsubstituted or substitutedlower alkyl or a heterocyclic radical, and R₃ and R₃′ have the meaningsas defined for a compound of formula I, can be prepared for example byreacting a compound of formula VI, wherein R₂ is hydrogen and R₃ and R₃′have the meanings as defined for a compound of formula I, with acompound of the formula R₂—OH, wherein R₂ is unsubstituted orsubstituted lower alkyl or a heterocyclic radical wherein thesubstituted lower alkyl or the heterocyclic radical is attached to thehydroxy group of R₂—OH via a carbon atom of the lower alkyl moiety orvia a carbon ring atom of the heterocyclic radical, respectively, e.g.under the Mitsunobu reaction conditions such as those described in:Mitsunobu, Oyo; Synthesis 1981, p. 1-27.

A compound of formula V, wherein R₅ is halogen or —S—CH₃ and n and Zhave the meanings as defined for a compound of formula I, can beprepared for example by reacting a compound of formula VII

wherein R₆ is halogen or —S—CH₃, respectively, and n and Z have themeanings as defined for a compound of formula I, withN,N-dimethylformamid-dimethylacetal, at elevated temperature, preferablyat around 100° C.

A compound of formula VII, wherein R₆ is halogen and n and Z have themeanings as defined for a compound of formula I, can be prepared forexample by reacting a compound of formula VIII

wherein n and Z have the meanings as defined for a compound of formulaI, with a compound of formula IX

wherein R₆ is halogen, in the presence of lithiumdiisopropylamide, in asuitable organic solvent or mixture of solvents, preferably starting thereaction at reduced temperature, preferably at around −75° C., andletting it to reach room temperature.

A compound of formula VII, wherein R₆ is —S—CH₃ and n and Z have themeanings as defined for a compound of formula I, can be prepared forexample by reacting a compound of formula X

wherein n and Z have the meanings as defined for a compound of formulaI, with a compound of formula IX, wherein R₆ is —S—CH₃, in the presenceof lithiumdiisopropylamide, in a suitable organic solvent or mixture ofsolvents, preferably starting the reaction at reduced temperature,preferably at around −75° C., and letting it to reach room temperature.

A compound of formula X, wherein n and Z have the meanings as definedfor a compound of formula I, can be prepared for example by reacting acompound of formula XI

wherein Hal is halogen, such as chloro, and n and Z have the meanings asdefined for a compound of formula I, with N—O-dimethylhydroxylamine HClin CH₂Cl₂, e.g. under those conditions described for the analogousprocedure in Nahm, Steven; Weinreb, Steven M.; Tetrahedron Lett.; 1981;22 (39); 3815-3818.

The remaining starting materials are known, capable of being preparedaccording to known processes, or commercially available; or inparticular, they can be prepared using processes as described in theExamples.

Pharmaceutical Compositions, Methods, and Uses:

The present invention relates also to pharmaceutical compositions thatcomprise a compound of formula I, or a pharmaceutically acceptable saltthereof, as active ingredient and that can be used especially in thetreatment of the diseases mentioned at the beginning. Compositions forenteral administration, such as nasal, buccal, rectal or, especially,oral administration, and for parenteral administration, such asintravenous, intramuscular or subcutaneous administration, towarm-blooded animals, especially humans, are especially preferred. Thecompositions contain the active ingredient alone or, preferably,together with a pharmaceutically acceptable carrier. The dosage of theactive ingredient depends upon the disease to be treated and upon thespecies, its age, weight, and individual condition, the individualpharmacokinetic data, and the mode of administration.

The present invention also relates to pro-drugs of a compound of formulaI that convert in vivo to the compound of formula I as such. Anyreference to a compound of formula I is therefore to be understood asreferring also to the corresponding pro-drugs of the compound of formulaI, as appropriate and expedient.

The invention relates also to compounds of formula I, or apharmaceutically acceptable salt thereof, as such or in the form of apharmaceutical composition, for use in a method for the prophylactic orespecially therapeutic treatment of the human or animal body, to aprocess for the preparation thereof (especially in the form ofcompositions for the treatment of tumours) and to a method of treatingproliferative diseases, primarily tumour diseases, especially thosementioned above.

The invention relates also to processes and to the use of compounds offormula I, or a pharmaceutically acceptable salt thereof, for thepreparation of pharmaceutical compositions which comprise compounds offormula I, or a pharmaceutically acceptable salt thereof, as activecomponent (active ingredient).

If desired, the said pharmaceutical compositions may also containfurther active components, for example cytostatics, and/or may be usedin combination with known therapeutic processes, for example theadministration of hormones or radiation.

Preference is given for a pharmaceutical composition which is suitablefor administration to a warm-blooded animal, especially humans orcommercially useful mammals suffering from a disease which responds toan inhibition of a protein tyrosine kinase, especially to a dualinhibition of EGF- and VEGF-receptor family members, especially aneoplastic disease, comprising an effective quantity of a compound offormula I for the inhibition of a protein tyrosine kinase, especiallyfor the dual inhibition of EGF- and VEGF-receptor family members, or apharmaceutically acceptable salt thereof, together with at least onepharmaceutically acceptable carrier.

A pharmaceutical composition for the prophylactic or especiallytherapeutic management of neoplastic and other proliferative diseases ofa warm-blooded animal, especially a human or a commercially usefulmammal requiring such treatment, especially suffering from such adisease, comprising as active ingredient in a quantity that isprophylactically or especially therapeutically active against saiddiseases a compound of formula I, or a pharmaceutically acceptable saltthereof, is likewise preferred.

The pharmaceutical compositions comprise from approximately 1% toapproximately 95% active ingredient, single-dose administration formscomprising in the preferred embodiment from approximately 20% toapproximately 90% active ingredient and forms that are not ofsingle-dose type comprising in the preferred embodiment fromapproximately 5% to approximately 20% active ingredient. Unit dose formsare, for example, coated and uncoated tablets, ampoules, vials,suppositories or capsules. Examples are capsules containing from about0.05 g to about 1.0 g of active substance.

The pharmaceutical compositions of the present invention are prepared ina manner known per se, for example by means of conventional mixing,granulating, coating, dissolving or lyophilising processes.

The invention relates likewise to a process or a method for thetreatment of one of the pathological conditions mentioned hereinabove,especially a disease which responds to an inhibition of a proteintyrosine kinase, especially to a dual inhibition of EGF- andVEGF-receptor family members, especially a corresponding neoplasticdisease. The compounds of formula I, or pharmaceutically acceptablesalts thereof, can be administered as such or in the form ofpharmaceutical compositions, prophylactically or therapeutically,preferably in an amount effective against the said diseases, to awarm-blooded animal, for example a human, requiring such treatment, thecompounds especially being used in the form of pharmaceuticalcompositions. In the case of an individual having a bodyweight of about70 kg the daily dose administered is from approximately 0.1 g toapproximately 5 g, preferably from approximately 0.5 g to approximately2 g, of a compound of the present invention.

The present invention relates especially also to the use of a compoundof formula I, or a pharmaceutically acceptable salt thereof, especiallya compound of formula I which is said to be preferred, or apharmaceutically acceptable salt thereof, as such or in the form of apharmaceutical composition with at least one pharmaceutically acceptablecarrier, for the therapeutic and also prophylactic management of one ormore of the diseases mentioned hereinabove, preferably a disease whichresponds to an inhibition of a protein tyrosine kinase, especially to adual inhibition of EGF- and VEGF-receptor family members, especially aneoplastic disease, in particular if the said disease responds to aninhibition of a protein tyrosine kinase, especially to a dual inhibitionof EGF- and VEGF-receptor family members.

The present invention relates especially also to the use of a compoundof formula I, or a pharmaceutically acceptable salt thereof, especiallya compound of formula I which is said to be preferred, or apharmaceutically acceptable salt thereof, for the preparation of apharmaceutical composition for the therapeutic and also prophylacticmanagement of one or more of the diseases mentioned hereinabove,especially a neoplastic disease, in particular if the disease respondsto an inhibition of a protein tyrosine kinase, especially to a dualinhibition of EGF- and VEGF-receptor family members.

A compound of formula I may also be used to advantage in combinationwith other antiproliferative agents. Such antiproliferative agentsinclude, but are not limited to aromatase inhibitors, antiestrogens,topoisomerase I inhibitors, topoisomerase II inhibitors, microtubuleactive agents, alkylating agents, histone deacetylase inhibitors,farnesyl transferase inhibitors, COX-2 inhibitors, MMP inhibitors, mTORinhibitors, antineoplastic antimetabolites, platin compounds, compoundsdecreasing the protein kinase activity and further anti-angiogeniccompounds, gonadorelin agonists, anti-androgens, bengamides,bisphosphonates, antiproliferative antibodies and temozolomide(TEMODAL®).

The term “aromatase inhibitors” as used herein relates to compoundswhich inhibit the estrogen production, i.e. the conversion of thesubstrates androstenedione and testosterone to estrone and estradiol,respectively. The term includes, but is not limited to steroids,especially exemestane and formestane and, in particular, non-steroids,especially aminoglutethimide, vorozole, fadrozole, anastrozole and, veryespecially, letrozole. Exemestane can be administered, e.g., in the formas it is marketed, e.g. under the trademark AROMASIN™. Formestane can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark LENTARON™. Fadrozole can be administered, e.g., in the form asit is marketed, e.g. under the trademark AFEMA™. Anastrozole can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark ARIMIDEX™. Letrozole can be administered, e.g., in the form asit is marketed, e.g. under the trademark FEMARA™ or FEMAR™.Aminoglutethimide can be administered, e.g., in the form as it ismarketed, e.g. under the trademark ORIMETEN™.

A combination of the invention comprising an antineoplastic agent whichis an aromatase inhibitor is particularly useful for the treatment ofhormone receptor positive breast tumours.

The term “antiestrogens” as used herein relates to compounds whichantagonize the effect of estrogens at the estrogen receptor level. Theterm includes, but is not limited to tamoxifen, fulvestrant, raloxifeneand raloxifene hydrochloride. Tamoxifen can be administered, e.g., inthe form as it is marketed, e.g. under the trademark NOLVADEX™.Raloxifene hydrochloride can be administered, e.g., in the form as it ismarketed, e.g. under the trademark EVISTA™. Fulvestrant can beformulated as disclosed in U.S. Pat. No. 4,659,516 or it can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark FASLODEX™.

The term “topoisomerase I inhibitors” as used herein includes, but is,not limited to topotecan, irinotecan, 9-nitrocamptothecin and themacromolecular camptothecin conjugate PNU-166148 (compound A1 inWO99/17804). Irinotecan can be administered, e.g., in the form as it ismarketed, e.g. under the trademark CAMPTOSAR™. Topotecan can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark HYCAMTIN™.

The term “topoisomerase II inhibitors” as used herein includes, but isnot limited to the antracyclines doxorubicin (including liposomalformulation, e.g. CAELYX™), epirubicin, idarubicin and nemorubicin, theanthraquinones mitoxantrone and losoxantrone, and the podophillotoxinesetoposide and teniposide. Etoposide can be administered, e.g., in theform as it is marketed, e.g. under the trademark ETOPOPHOS™. Teniposidecan be administered, e.g., in the form as H is marketed, e.g. under thetrademark VM 26BRISTOL™. Doxorubicin can be administered, e.g., in theform as it is marketed, e.g. under the trademark ADRIBLASTIN™.Epirubicin can be administered, e.g., in the form as it is marketed,e.g. under the trademark FARMORUBICIN™. Idarubicin can be administered;e.g., in the form as it is marketed, e.g. under the trademark ZAVEDOS™.Mitoxantrone can be administered, e.g., in the form as it is marketed,e.g. under the trademark NOVANTRON™.

The term “microtubule active agents” relates to microtubule stabilizingand microtubule destabilizing agents including, but not limited to thetaxanes paclitaxel and docetaxel, the vinca alkaloids, e.g.,vinblastine, especially vinblastine sulfate, vincristine especiallyvincristine sulfate, and vinorelbine, discodermolide and epothilones,such as epothilone B and D. Docetaxel can be administered, e.g., in theform as it is marketed, e.g. under the trademark TAXOTERE™. Vinblastinesulfate can be administered, e.g., in the form as it is marketed, e.g.under the trademark VINBLASTIN R.P.™. Vincristine sulfate can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark FARMISTIN™. Discodermolide can be obtained, e.g., as disclosedin U.S. Pat. No. 5,010,099.

The term “alkylating agents” as used herein includes, but is not limitedto cyclophosphamide, ifosfamide and melphalan. Cyclophosphamide can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark CYCLOSTIN™. Ifosfamide can be administered, e.g., in the formas it is marketed, e.g. under the trademark HOLOXAN™.

The term “histone deacetylase inhibitors” relates to compounds whichinhibit the histone deacetylase and which possess antiproliferativeactivity.

The term “farnesyl transferase inhibitors” relates to compounds whichinhibit the farnesyl transferase and which possess antiproliferativeactivity.

The term “COX-2 inhibitors” relates to compounds which inhibit thecyclooxygenase type 2 enyzme (COX-2) and which possess antiproliferativeactivity such as celecoxib (Celebrex®), rofecoxib (Vioxx®) andlumiracoxib (COX189).

The term “MMP inhibitors” relates to compounds which inhibit the matrixmetalloproteinase (MMP) and which possess antiproliferative activity.

The term “mTOR inhibitors” relates to compounds which inhibit themammalian target of rapamycin (mTOR) and which possess antiproliferativeactivity such as sirolimus (Rapamune®), everolimus (Certican™), CCI-779and ABT578.

The term “antineoplastic antimetabolites” includes, but is not limitedto 5-fluorouracil, tegafur, capecitabine, cladribine, cytarabine,fludarabine phosphate, fluorouridine, gemcitabine, 6-mercaptopurine,hydroxyurea, methotrexate, edatrexate and salts of such compounds, andfurthermore ZD 1694 (RALTITREXED™), LY231514 (ALIMTA™), LY264618(LOMOTREXOL™) and OGT719.

The term “platin compounds” as used herein includes, but is not limitedto carboplatin, cisplatin and oxaliplatin. Carboplatin can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark CARBOPLAT™. Oxaliplatin can be administered, e.g., in the formas it is marketed, e.g. under the trademark ELOXATIN™.

The term “compounds decreasing the protein kinase activity and furtheranti-angiogenic compounds” as used herein includes, but is not limitedto compounds which decrease the activity of e.g. the VascularEndothelial Growth Factor (VEGF), the Epidermal Growth Factor (EGF),c-Src, protein kinase C, Platelet-derived Growth Factor (PDGF), Bcr-Abltyrosine kinase, c-kit, Flt-3 and insulin-like Growth Factor I Receptor(IGF-IR) and Cyclin-dependent kinases (CDKs), and anti-angiogeniccompounds having another mechanism of action than decreasing the proteinkinase activity.

Compounds which decrease the activity of VEGF are especially compoundswhich inhibit the VEGF receptor, especially the tyrosine kinase activityof the VEGF receptor, and compounds binding to VEGF, and are inparticular those compounds, proteins and monoclonal antibodiesgenerically and specifically disclosed in WO 98/35958 (describingcompounds of formula I), WO 00/09495, WO 00/27820, WO 00/59509, WO98/11223, WO 00/27819, WO 01155114, WO 01/58899 and EP 0 769 947; thoseas described by M. Prewett et al in Cancer Research 59 (1999) 5209-5218,by F. Yuan et al in Proc. Natl. Acad. Sci. USA, vol. 93, pp.14765-14770, December 1996, by Z. Zhu et al in Cancer Res. 58, 1998,3209-3214, and by J. Mordenti et al in Toxicologic Pathology, vol. 27,no. 1, pp 14-21, 1999; in WO 00/37502 and WO 94/10202; Angiostatin™,described by M. S. O'Reilly et al, Cell 79, 1994, 315-328; andEndostatin™, described by M. S. O'Reilly et al, Cell 88, 1997, 277-285;compounds which decrease the activity of EGF are especially compoundswhich inhibit the EGF receptor, especially the tyrosine kinase activityof the EGF receptor, and compounds binding to EGF, and are in particularthose compounds generically and specifically disclosed in WO 97/02266(describing compounds of formula IV), EP 0 564 409, WO 99/03854, EP0520722, EP 0 566 226, EP 0 787 722, EP 0 837 063, WO 98/10767, WO97/30034, WO 97/49688, WO 97/38983 and, especially, WO 96/33980;compounds which decrease the activity of c-Src include, but are notlimited to, compounds inhibiting the c-Src protein tyrosine kinaseactivity as defined below and to SH2 interaction inhibitors such asthose disclosed in WO97/07131 and WO97/08193; compounds inhibiting thec-Src protein tyrosine kinase activity include, but are not limited to,compounds belonging to the structure classes of pyrrolopyrimidines,especially pyrrolo[2,3-d]pyrimidines, purines, pyrazopyrimidines,especially pyrazo[3,4-d]pyrimidines, pyrazopyrimidines, especiallypyrazo[3,4-d]pyrimidines and pyridopyrimidines, especiallypyrido[2,3-d]pyrimidines. Preferably, the term relates to thosecompounds disclosed in WO 96/10028, WO 97/28161, WO97/32879 andWO97/49706; compounds which decreases the activity of the protein kinaseC are especially those staurosporine derivatives disclosed in EP 0 296110 (pharmaceutical preparation described in WO 00/48571) whichcompounds are protein kinase C inhibitors; further specific compoundsthat decrease protein kinase activity and which may also be used incombination with the compounds of the present invention are Imatinib(Gleevec®/Glivec®), PKC412, Iressa™ (ZD1839), PKI166, PTK787, ZD6474,GW2016, CHIR-200131, CEP-7055/CEP-5214, CP-547632 and KRN-633;anti-anglogenic compounds having another mechanism of action thandecreasing the protein kinase activity include, but are not limited toe.g. thalidomide (THALOMID), celecoxib (Celebrex), SU5416 and ZD6126.

The term “gonadorelin agonist” as used herein includes, but is notlimited to abarelix, goserelin and goserelin acetate. Goserelin isdisclosed in U.S. Pat. No. 4,100,274 and can be administered, e.g., inthe form as it is marketed, e.g. under the trademark ZOLADEX™. Abarelixcan be formulated, eg. as disclosed in U.S. Pat. No. 5,843,901.

The term “anti-androgens” as used herein includes, but is not limited tobicalutamide (CASODEX™), which can be formulated, e.g. as disclosed inU.S. Pat. No. 4,636,505.

The term “bengamides” relates to bengamides and derivatives thereofhaving aniproliferative properties.

The term “bisphosphonates” as used herein includes, but is not limitedto etridonic acid, clodronic acid, tiludronic acid, pamidronic acid,alendronic acid, ibandronic acid, risedronic acid and zoledronic acid.“Etridonic acid” can be administered, e.g., in the form as it ismarketed, e.g. under the trademark DIDRONEL™. “Clodronic acid” can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark BONEFOS™. “Tiludronic acid” can be administered, e.g., in theform as it is marketed, e.g. under the trademark SKELID™. “Pamidronicacid” can be administered, e.g., in the form as it is marketed, e.g.under the trademark AREDIA™. “Alendronic acid” can be administered,e.g., in the form as it is marketed, e.g. under the trademark FOSAMAX™.“Ibandronic acid” can be administered, e.g., in the form as it ismarketed, e.g. under the trademark BONDRANAT™. “Risedronic acid” can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark ACTONEL™. “Zoledronic acid” can be administered, e.g., in theform as it is marketed, e.g. under the trademark ZOMETA™.

The term “antiproliferative antibodies” as used herein includes, but isnot limited to trastuzumab (Herceptin™), Trastuzumab-DM1, erlotinib(Tarceva™), bevacizumab (Avastin™), rituximab (Rituxan®), PRO64553(anti-CD40) and 2C4 Antibody.

For the treatment of AML, compounds of formula I can be used incombination with standard leukemia therapies, especially in combinationwith therapies used for the treatment of AML. In particular, compoundsof formula I can be administered in combination with e.g.farnesyltransferase inhibitors and for other drugs used for thetreatment of AML, such as Daunorubicin, Adriamycin, Ara-C, VP-16,Teniposide, Mitoxantrone, Idarubicin, Carboplatinum and PKC412.

The structure of the active agents identified by code nos., generic ortrade names may be taken from the actual edition of the standardcompendium “The Merck Index” or from databases, e.g. PatentsInternational (e.g. IMS World Publications).

The above-mentioned compounds, which can be used in combination with acompound of formula I, can be prepared and administered as described inthe art such as in the documents cited above.

EXAMPLES

The following Examples serve to illustrate the invention withoutlimiting its scope.

Temperatures are measured in degrees Celsius. Unless otherwiseindicated, the reactions take place at RT.

The R_(f) values which indicate the ratio of the distance moved by eachsubstance to the distance moved by the eluent front are determined onsilica gel thin-layer plates (Merck, Darmstadt, Germany) by thin-layerchromatography using the respective named solvent systems.

Analytical HPLC Conditions:

System 1:

Linear gradient 20-100% CH₃CN [0.1% trifluoroacetic acid (TFA)] and H₂O(0.1% TFA) in 7 min+2 min 100% CH₃CN (0.1% TFA); detection at 215 nm,flow rate 1 mL/min at 30° C. Column: Nucleosil 100-3 C18HD (125×4 mm).

System 2:

Linear gradient 2-100% CH₃CN (0.1% TFA) and H₂O (0.1% TFA) in 10 min+2min 100% CH₃CN (0.1% TFA); detection at 216 nm, flow rate 2 mL/min atrt. Column: Nucleosil 100-3 C18HD (125×4 mm).

System 3:

Linear gradient 10→90% CH₃CN in H₂O (0.1% TFA) in 10 min; detection at215, 230, 254, 280 nm, flow rate 2 mL/min at 20° C. Column: Nova-PakC18HD (150×3.9 mm).

System 4:

10% CH₃CN in H₂O (0.1% TFA) for 5 min, then linear gradient 10→90% CH₃CNin H₂O (0.1% TFA) in 25 min; detection at 215, 230, 254, 280 nm, flowrate 2 mL/min at 20° C. Column: Nova-Pak C18HD (150×3.9 mm).

System 5:

10% CH₃CN/90% H₂O (0.1% TFA) for 1 min, then linear gradient 10→70%CH₃CN in H₂O (0.1% TFA) in 19 min, then hold 70% CH₃CN in H₂O (0.1% TFA)for 15 min; detection at 254 nm, flow rate 1.5 mL/min at 20° C. Column:Nova-Pak C18 (4.6×250 mm).

System XS:

-   Column: (50×4.6 mm) packed with reversed-phase material    C18-Nucleosil (Interchrom UP3ODB-5QS, Optisphere 3 μM ODB).    Detection by UV absorption at 215 nm. The retention times (t_(R))    are given in minutes. Flow rate: 2 ml/min.-   Gradient: 15%→100% a) in b) for 2.25 min+1.25 min 100% a). a):    Acetonitrile+0.1% TFA; b): water+0.1% TFA.

System XI:

-   Column: (250×4.6 mm) packed with reversed-phase materal C18Nucleosil    (5 μm mean particle size, with silica gel covalently derivatized    with octadecylsilanes, Macherey & Nagel, Düren, Germany). Detection    by UV absorption at 215 nm. The retention times (t_(R)) are given in    minutes. Flow rate: 1 ml/min.-   Gradient: 20%→100% a) in b) for 14 min+5 min 100% a). a):    Acetonitrile+0.1% TFA; b): water+0.1% TFA.

System X2:

-   Column: (250×4.6 mm) packed with reversed-phase material    C18-Nucleosil (5 μm mean particle size, with silica gel covalently    derivatized with octadecylsilanes, Macherey & Nagel, Düren,    Germany). Detection by UV absorption at 215 nm. The retention times    (t_(R)) are given in minutes. Flow rate: 1 ml/min.-   Gradient: 5%→40% a) in b) for 9 min+7 min 100% a). a):    Acetonitrile+0.1% TFA; b): water+0.1% TFA.

Abbreviations: abs. absolute approx. approximately aq. Aqueous BOCtert-butoxycarbonyl BOP(benzotriazol-1-yloxy)-tris(dimethylamino)phosphonium-hexafluorophosphate b.p. boiling point DCM dichloromethane DEAD diethylazodicarboxylate DMF N,N-dimethylformamide DMF-DMAdimethylformamide-dimethylacetal (FLUKA) Eq. equivalent(s) ESIelectrospray ionization ES-MS electron spray-mass spectroscopy Et ethylh hour(s) HOAc acetic acid m-CPBA 3-chloroperoxybenzoic acid MeOHmethanol mm minute(s) m.p. melting point Py-BOPbenzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphatert room temperature satd. saturated THF tetrahydrofuran TLC thin-layerchromatography TOF-MS time-of-flight mass spectroscopy t_(R) retentiontimes

Example 1

{4-[3-(4-Chloro-phenyl)1H-pyrazol-4yl]-pyrimidin-2-yl}-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine

The solution of 150 mg (0.515 mMol) of2-chloro-4-[3-(4-chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidine in 5 mL of1,4-dioxanes (Merck p.a. 9671) at rt is treated with 99 mg of4-(4-methyl-piperazin-1-yl)-phenylamine (0,515 mMol, 1 Eq.) and 235 mg(2.06 mMol; 202 μl; 4 Eq.) of HCl (32%) (Fluka puriss 84416). The yellowsuspension is stirred for 24 h at 100° C. After cooling to rt, thesupernatant is decanted and discarded. The smeary residue is treatedwith 10 ml of NaHCO₃ satd. solution and 10 ml of ethyl acetates. Theprecipitated crude product is filtered off and dried at 60° C. underreduced pressure. The combined organic layers are re-extracted withwater, dried (Na₂SO₄), and evaporated to obtain additional crudeproduct. The combined crude products are purified by means of columnchromatography over silica gel (Si60 (0,040-0,063 mm) Merck); elutingwith CH₂Cl₂/CH₃OH/NH₄OH (9:1:0.1). Final purification is done bysuspending the obtained beige crystals in CH₂Cl₂/CH₃OH (1:1) to obtain{4-[3-(4-chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(4-methyl-piperazin-1-yl)-phenyl]-amineas pure crystals.

Title compound: m.p.: 282-284° C.; ES-MS: 444.3 [M−H]⁻; single peak att_(R)=3.45 min (System 1); R_(f)=0.37 (CH₂Cl₂/MeOH/NH₃ 90:10:1).

4-(4-Methyl-piperazin-1-yl)-phenylamine is prepared as follows:

Step A: 50 g (0.247 Mol) of 1-Bromo-4-nitro-benzene and 55 mL. (0.495Mol) of 1-methyl-piperazine are heated for 26 h at 80° C. After cooling,the reaction mixture is taken up in water and extracted with CH₂Cl₂CH₃OH(8:2). The combined organic layers are dried (Na₂SO₄), filtered andevaporated under reduced pressure. The crude product is recrystallizedfrom ethanol to obtain 1-methyl-4-(4-nitro-phenyl)-piperazine. Titlecompound: ES-MS: 443.0 [M+H]⁺; R_(f)=0.38 (CH₂Cl₂/MeOH 9:1).

Step B: 44.3 g (0.2 Mol) of 1-Methyl-4-(4-nitro-phenyl)-piperazine isdissolved in 1200 mL of CH₃OH and subjected to catalytic hydration at rtusing Raney-Ni (10 g) as catalyst. After filtration over Celite, thecrude product is purified via solid-distillation (0.16 mbar, 180° C.;heat temp 125° C.) to obtain 4-(4-methyl-piperazin-1-yl)-phenylamine.Title compound: ES-MS: 192.1 [M+H]⁺; single peak at t_(R)=1.08 min(System 1); R_(f)=0.33 (CH₂Cl₂/MeOH 4:1).

Step 1.1: 2-Chloro-4-methyl-pyrimidine

200 g (227 Mol) of 2,4-Dichloro-6-methylpyrimidine is suspended in 2 lof water/ethanol (1:1) and heated to 50° C. under stirring. Upondissolution, 331.3 g (5.07 Mol; 4.13 Eq.) of zinc dust (Fluka 96454) isadded, followed by 10 crystals of iodine (Merck p.a. 4761.0100). Afterstirring for 20 h at 50° C., the grey suspension is filtered over HYFLO(Hyflo Super Cel®; Fluka), washed with few ethanol and diluted with 800mL of water. The mixture is extracted with tert-butylmethyl ether, theorganic layer washed with brine, dried (Na₂SO₄), filtered and evaporatedunder reduced pressure at 40° C. to obtain 2-chloro-4-methyl-pyrimidineas beige crystals.

Title compound: m.p.: 44-47° C.; single peak at t_(R)=2.92 min (System1); R_(f)=0.5 (ethyl acetate).

Step 1.2: 1-(4-Chloro-phenyl)-2-(2-chloro-pyrimidin-4-yl)-ethanone

To the solution of 19 mL (38 mMol) of LDA (Lithiumdiisopropylamide) (˜2M in THF/heptan/ethylbenzene; FLUKA pract 62491) at −74° C., under aflow of Argon, is added dropwise a solution of2-chloro-4-methyl-pyrimidine (4.11 g; 32 mMol) in 20 mL of THF abs.After stirring the beige solution at −74° C. for 3 h, 7.01 g (38 mMol)of ethyl-4-chlorobenzoate (LANCASTER 1407) is added within 30 min. Thereaction is continued for 21 h, allowing temperature to reach rt. 100 mLof water is added slowly followed by extraction with ethyl acetate. Thecombined organic layers are washed with water, dried (Na₂SO₄) andfiltered. After removal of the solvent under reduced pressure, crudeproduct is obtained. The crude product is suspended in ethylacetate/hexanes (1:2). After filtering off and drying at 60° C., theorange crystals are recrystallized from methanol to obtain pure,yellowish 1-(4-chloro-phenyl)-2-(2-chloro-pyrimidin-4-yl)-ethanone.

Title compound: m.p.: 145-146° C.; ES-MS: 267 [M+H]⁺; single peak att_(R)=6.33 min (System 1).

Step 1.3: 2-Chloro-4-[3-(4-chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidine

3.67 g (13.74 mMol) of1-(4-Chloro-phenyl)-2-(2-chloro-pyrimidin-4-yl)-ethanone is suspended in91.6 mL (50 Eq.) of N,N-dimethylformamid-dimethylacetal (Fluka puriss.40271) and stirred for 2 h at 100° C. The dark brownish solution isfreed from solvent under high vacuum at 30° C. The crude product,(Z)-1-(4-chloro-phenyl)-2-(2-chloro-pyrimidin-4-yl)-3-dimethylamino-propenone,is used for the next step without purification. To the solution of 5.42g (14.2 mMol) of(Z)-1-(4-chloro-phenyl)-2-(2-chloro-pyrimidin-4-yl)-3-dimethylamino-propenonein 30 mL of ethanol 0.785 g (0.763 mL; 15.69 mMol, 1.1 Eq.) of hyrazinemonohydrate (Fluka 53850) is added at rt. After stirring 45 min at rt,the yellow crystals are filtered off, washed with ethanol and dried at60° C. under vacuum. The crude product is purified by recrystallizationfrom methanol to obtain2-chloro-4-[3-(4-chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidine as slightlyyellowish crystals.

Title compound: m.p.: 246-247° C. (decomposition temperature); ES-MS:289 [M+H]⁺; single peak at t_(R)=5.81 min (System 1); R_(f)=0.2(CH₂Cl₂/MeOH 95:5).

Example 2{4-[3-(4-Chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(2-dimethyl-amino-ethoxy)-phenyl]-amine

The title compound is prepared as described in Example 1 using4-(2-dimethylamino-ethoxy)-phenylamine.

4-(2-Dimethylamino-ethoxy)-phenylamine is prepared in 3 steps fromp-nitrophenol:

Step A: To the solution of 27.83 g (0.2 Mol) of 4-nitro-phenol (Fluka73560) in 420 mL of acetone is added 55.28 g (0.4 Mol) of potassiumcarbonate, 143.42 g (1 Mol) of 1-bromo-2-chloro-ethane, 0.55 g (0.0033Mol) of potassium iodide and 0.28 g (0.00087 Mol) of tetrabutyl-ammoniumbromide (Fluka 86860). The resulting suspension is refluxed for 67 h.After removing the solvent under reduced pressure, the residue is takenup into ethyl acetate and washed with water. The combined organic layersare dried (Na₂SO₄), filtered and concentrated under reduced pressure.After trituration of the residue with ligroin, the crystals are filteredoff to obtain 1-(2-chloro-ethoxy)-4-nitro-benzene.

Step B: 36 g (0.178 Mol) of 1-(2-Chloro-ethoxy)-4-nitro-benzene isdissolved in 360 mL of ethanol and subjected to catalytic hydration atrt using PtO₂ (1.5 g) as catalyst. The resulting suspension is dilutedwith CH₂Cl₂, filtered, and concentrated to approx. 150 mL. After coolingto 0° C. the crystals are filtered off, washed and dried at 60° C. undervacuum to obtain 4-(2-chloro-ethoxy)-phenylamine. Title compound: m.p.:87-91° C.; ES-MS: 172 [M+H]⁺; single peak at t_(R)=2.73 min (System 1).

Step C: 11.15 g (0.065 Mol) of 4-(2-Chloro-ethoxy)-phenylamine issuspended in 150 mL (1.18 Mol) of dimethylamine (40% in water; Fluka38940) and heated under stirring in a steel pressure reactor at 4 barfor 21 h. After cooling the reaction mixture is diluted with 150 mL of2N NaOH and extracted with ethyl acetate. The combined organic layersare washed with water, dried (Na₂SO₄), filtered and evaporated underreduced pressure to obtain 4-(2-dimethylamino-ethoxy)-phenylamine. Titlecompound: ES-MS: 181 [M+H]⁺; single peak at t_(R)=1.10 min (System 1).

Example 3{4-[3-(4-Chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(2-diethylamino-ethoxy)phenyl]-amine

The title compound is prepared as described in Example 1 using4-(2-diethylamino-ethoxy)-phenylamine.

4-(2Diethylamino-ethoxy)-phenylamine is prepared as follows:

Step A: To the solution of 8.0 g (51 mMol) of 1-chloro-4-nitrobenzeneand 6.0 g (6.8 mL; 51 mMol) of 2-diethylamino-ethanol in 50 mL of DMF at0° C. is added 2.7 g of NaH portionwise over 2 h. After stirring anotherhour at rt, the reaction mixture is poured onto 300 mL of water andstirred. After filtering off some crystalline product, the aqeous layersare extracted with ethyl acetate. The combined organic layers are driedand evaporated to obtain diethyl-[2-(4-nitro-phenoxy)-ethyl]-amine.Title compound: ES-MS: 239 [M+H]⁺; single peak at t_(R)=5.1 min (System2).

Step B: 10 g (42 mMol) of Diethyl-[2-(4-nitro-phenoxy)-ethyl]-amine isdissolved in 100 mL of ethanol and subjected to catalytic hydration atrt using 894 mg of Pd/C. After filtration trough HYFLO and removal ofthe solvent under reduced pressure, the crude product is purified bybulb-to-bulb distillation (140° C.) to obtain4-(2-diethylamino-ethoxy)-phenylamine. Title compound: ES-MS: 209[M+H]⁺; single peak at t_(R)=2.3 min (System 2).

Example 4{4-[3-(4-Chloro-phenyl)-1H-pyrazol-4yl]-pyrimidin-2-yl}-[4-(2-morpholinyl-4-yl-ethoxy)-phenyl]-amine

The title compound is prepared as described in Example 1 using4-(2-morpholin-4-yl-ethoxy)-phenylamine.

4-(2-Morpholin-4-yl-ethoxy)-phenylamine is prepared as follows:

Step A: To the solution of 8.0 g (51 mMol) of 1-chloro-4-nitrobenzeneand 6.7 g (6.3 mL; 51 mMol) of N-hydroxyethyl-morpholine in 50 mL of DMFat 0° C. is added 2.7 g of NaH portionwise over 2.5 h. After stirringanother hour at rt, the reaction mixture is poured onto 200 mL of waterand stirred. The precipitated crystals are filtered and dried at 60° C.under vacuum to obtain 4-[2-(4-nitro-phenoxy)-ethyl]-morpholine. Titlecompound: ES-MS: 253 [M+H]⁺; single peak at t_(R)=4.8 min (System 2).

Step B: 8.1 g (32 mMol) of 4-[2-(4-Nitro-phenoxy)-ethyl]-morpholine isdissolved in 100 mL of ethanol and subjected to catalytic hydration atrt using 681 mg of Pd/C. After filtration trough HYFLO and removal ofthe solvent under reduced pressure, the crude product is purified bybulb-to-bulb distillation (0.13 mbar: 200° C.) to obtain4-(2-morpholin-4-yl-ethoxy)-phenylamine. Title compound: ES-MS: 223[M+H]⁺; single peak at t_(R)=3 min (System 2).

Example 5{4-[3-(3-Chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(2-dimethylamino-ethoxy)-phenyl]-amine

The title compound is prepared as described in Example 1 using3-chloro-benzoic acid ethyl ester and4-(2-dimethylamino-ethoxy)-phenylamine (see Example 2).

3-Chloro-benzoic acid ethyl ester is prepared from 3-chloro-benzoic acidusing a standard protocol with ethanol/H₂SO₄ according to L.-F. Tietze &T. Eicher, Reactions and Syntheses in the Organic Chemistry Laboratory;University Science Books, Mill Valley, Calif., 1989). Title compound:single peak at t_(R)=7.29 min (System 1).

Example 6{4-[3-(3Chloro-phenyl)1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(2-morpholin-4yl-ethoxy)-phenyl]-amine

The title compound is prepared as described in Example 1 using3-chloro-benzoic acid ethyl ester (see Example 5) and4-(2-morpholin-4-yl-ethoxy)phenylamine (see Example 4).

Example 7{4-[3-(3-Chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(2-diethylamino-ethoxy)-phenyl]-amine

The title compound is prepared as described in Example 1 using3-chloro-benzoic acid ethyl ester (see Example 5) and4-(2-diethylamino-ethoxy)-phenylamine (see Example 3).

Example 8{(4-[3-(3-Chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine

The title compound is prepared as described in Example 1 using3-chloro-benzoic acid ethyl ester (see Example 5).

Example 9{4-[3-(4-Methoxy-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine

The title compound is prepared as described in Example 1 using4-methoxy-benzoic acid ethyl ester (Aldrich W24,200-4).

Example 10{4-[3-(4-Methoxy-phenyl)1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-amine

The title compound is prepared as described in Example 1 using4-methoxy-benzoic acid ethyl ester (Aldrich W24,200-4) and4-(2-morpholin-4yl-ethoxy)-phenylamine (see Example 4).

Example 11{4-[3-(4-Ethyl-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}[4-(4-methyl-piperazin-1-yl)-phenyl]-amine

The title compound is prepared as described in Example 1 using4-ethyl-benzoic acid ethyl ester.

4Ethyl-benzoic acid ethyl ester is prepared from 4-ethyl-benzoic acidusing a standard protocol with ethanol/H₂SO₄ according to L.-F. Tietze &T. Eicher, Reactions and Syntheses in the Organic Chemistry Laboratory;University Science Books, Mill Valley, Calif., 1989). Title compound:b.p. 132° C. (12 mm Hg); single peak at t_(R)=7.51 min (System 1).

Example 12[4-(2-Diethylamino-ethoxy)phenyl]-{4-[3-(4-ethyl-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-amine

The title compound is prepared as described in Example 1 using4-ethyl-benzoic acid ethyl ester (see Example 11) and4-(2-diethylamino-ethoxy)-phenylamine (see Example 3).

Example 13[4-(2-Diethylamino-ethoxy)-phenyl]-{4-[3-(4-methoxy-phenyl)-1H-pyrazol-4yl]-pyrimidin-2-yl}-amine

The title compound is prepared as described in Example 1 using4-methoxy-benzoic acid ethyl ester (Aldrich W24,200-4) and4-(2-diethylamino-ethoxy)-phenylamine (see Example 3).

Example 14[4-(2-Diethylamino-ethoxy)phenyl]-{4-[43-(3-methoxy-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-amine

The title compound is prepared as described in Example 1 using3-methoxy-benzoic acid ethyl ester and4-(2-diethylamino-ethoxy)-phenylamine (see Example 3).

3-Methoxy-benzoic acid ethyl ester is prepared from 3-methoxy-benzoicacid using a standard protocol with ethanol/H₂SO₄ according to L.-F.Tietze & T. Eicher, Reactions and Syntheses in the Organic ChemistryLaboratory; University Science Books, Mill Valley, Calif., 1989). Titlecompound: b.p. 151° C. (25 mm Hg); single peak at t_(R)=6.51 min (System1).

Example 15{4-[3-(3-Methoxy-phenyl)-1H-pyrazol-4yl]pyrimidin-2-yl}-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-amine

The title compound is prepared as described in Example 1 using3-methoxy-benzoic acid ethyl ester (see Example 14) and4-(2-morpholin-4-yl-ethoxy)-phenylamine (see Example 4).

Example 16{4-[3-(3-Methoxy-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine

The title compound is prepared as described in Example 1 using3-methoxy-benzoic acid ethyl ester (see Example 14).

Example 17[4-(2-Dimethylamino-ethoxy)-phenyl]-{4-[3-(4-ethyl-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-amine

The title compound is prepared as described in Example 1 using4-ethyl-benzoic acid ethyl ester (see Example 11) and4-(2-dimethylamino-ethoxy)-phenylamine (see Example 2).

Example 18[4-(4-Methyl-piperazin-1yl)-phenyl]-[4-(3-m-tolyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine

The title compound is prepared as described in Example 1 usingethyl-3-methylbenzoate (Aldrich 25,305-7).

Example 19[4-(2-Diethylamino-ethoxy)-phenyl]-[4-(3-m-tolyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine

The title compound is prepared as described in Example 1 usingethyl-3-methylbenzoate (Aldrich 25,305-7) and4-(2-diethylamino-ethoxy)-phenylamine (see Example 3).

Example 20[4-(2-Dimethylamino-ethoxy)-phenyl]-[4-(3-m-tolyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine

The title compound is prepared as described in Example 1 usingethyl-3-methylbenzoate (Aldrich 25,3057) and4-(2-dimethylamino-ethoxy)-phenylamine (see Example 2).

Example 21{4-[3-(3,4-Dichloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(2-dimethylamino-ethoxy)-phenyl]-amine

The title compound is prepared as described in Example 1 usingethyl-3,4-dichlorobenzoate and 4-(2-dimethylamino-ethoxy)-phenylamine(see Example 2).

Ethyl-3,4-dichlorobenzoate is prepared from 3,4-dichloro-benzoic acidusing a standard protocol with ethanol/H₂SO₄ according to L.-F. Tietze &T. Eicher, Reactions and Syntheses in the Organic Chemistry Laboratory;University Science Books, Mill Valley, Calif., 1989). Title compound:m.p.: 40-41° C.; single peak at t_(R)=7.89 min (System 1).

Example 22{4-[3-(3,4-Dichloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine

The title compound is prepared as described in Example 1 usingethyl-3,4-dichlorobenzoate (see Example 21).

Example 23{4-[3-(4-Benzyloxy-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(2-dimethylamino-ethoxy)-phenyl]-amine

The title compound is prepared as described in Example 1 usingethyl-4-(benzyloxy)benzoat (MAYBRIDGE 03-1741) and4-(2-dimethylamino-ethoxy)-phenylamine (see Example 2).

Example 244-(4-{2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}1H-pyrazol-3-yl)-phenol

The title compound is prepared as described in Example 1 usingethyl-4-(benzyloxy)benzoat (MAYBRIDGE 03-1741). The title compound isisolated as a side product due to the loss of the benzyl group.

Example 25[4-(4-Methyl-piperazin-1-yl)-phenyl]-[4-(3-p-tolyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine

The title compound is prepared as described in Example 1 usingethyl-p-toluate (Fluka 89909).

Example 26[4-(2-Dimethylamino-ethoxy)-phenyl]-[4-(3-p-tolyl-1H-pyrazolyl-4-yl)-pyrimidin-2-yl]-amine

The tile compound is prepared as described in Example 1 usingethyl-4-methylbenzoate (see Example 25) and4-(2-dimethylamino-ethoxy)-phenylamine (see Example 2).

Example 27{4-[3(4-Chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[3-(1-methyl-piperidin-4-ylmethoxy)-phenyl]-amine

The title compound is prepared as described in Example 1 using[3-(1-methyl-piperidin-4-ylmethoxy)-phenyl]-carbamic acid tert-butylester.

[3-(1-Methyl-piperidin-4-ylmethoxy)-phenyl]-carbamic acid tert-butylester is prepared as Follows:

To the solution of 3.04 g (14.51 mMol; 1.25 Eq.) of 3-N-BOC-Aminophenoland 3.81 9 (14.51 mMol; 1.25 Eq.) of triphenylphosphin (AldrichT8,440-9) under Argon in 30 mL of THF at 10° C. is added dropwise asolution of 2.26 mL (14.51 mMol) of diethyl-azodicarboxylate (95%; Fluka11624) in 6 mL of THF abs. After stirring for 10 min under ice cooling,a solution of 1.5 g (11.61 mMol; 1 Eq.) of 1-methyl-4piperidinemethanol(Chem Pacific; 33077*) in 6 mL of THF abs. is added and kept for 20 minat 10° C. After 15 h at rt, the solvent is removed under reduced pressure and the reaction mixture is purified by column chromatography oversilica gel [Si60 (0,040-0,063 mm) Merck], eluting withmethylenchlorid/methanol/NH₃ (25%_(aqua)) 70:10:0.8 to obtain[3-(1-methyl-piperidin-4-ylmethoxy)-phenyl]-carbamic acid tert-butylester. Title compound: ES-MS: 321.1 [M+H]⁺; single peak at t_(R)=4.63min (System 1).

* 1-Methyl-4-piperidinemethanol can alternatively be prepared frompiperidin-4-yl-methanol and formaldehyde (36% in water) under reductiveconditions (H₂/RaNi in CH₃OH) at rt.

Example 28{4-[3-(4-Chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(1-methyl-piperidin-4-ylmethoxy)-phenyl]-1-amine

The title compound is prepared as described in Example 1 using[4-(1-methyl-piperidin-4-ylmethoxy)-phenyl]-carbamic acid tert-butylester.

[4-(1-Methyl-piperidin-4-ylmethoxy)-phenyl]-carbamic acid tert-butylester is prepared as described for[3-(1-methyl-piperidin-4-ylmethoxy)-phenyl]-carbamic acid tert-butylester (see Example 27) using 4-N-BOC-Aminophenol (AstaTech; B56686).Title compound: ES-MS: 321.1 [M+H]⁺; single peak at t_(R)=4.55 min(System 1).

Example 29{4-[3-(4-Chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[3-(4-methyl-piperazin-1-yl)-phenyl]-amine

The title compound is prepared as described in Example 1 using3-(4-methyl-piperazin-1-yl)-phenylamine.

3-(4-Methyl-piperazin-1-yl)-phenylamine is prepared as described for4-(4-methyl-piperazin-1-yl)-phenylamine (see Example 1) using3-bromo-phenylamine.

Title compound: ES-MS: 192.0 [M+H]⁺; single peak at t_(R)=1.14 min(System 1).

Example 304-{4-[3-(4-Chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-ylamino}-benzoicacid

The title compound is prepared as described in Example 1 using4-aminobenzoic acid (Fluka 06930).

Example 31(4-{4-[3-(4-Chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-ylamino}-phenyl)-(4-methyl-piperazin-1-yl)-methanone

To the suspension of 600 mg (1.53 mMol; 1 Eq.) of4-{4-[3-(4-chloro-phenyl)1H-pyrazol-4-yl]-pyrimidin-2-ylamino}-benzoicacid (Example 30) in 5 mL of DMF at rt is added 186 mg (202 μL; 1.83mMol; 1.2 Eq.) of N-methylmorpholine ( Fluka 67869); 677 mg (1.53 mMol;1 Eq.) of BOP (Fluka 12802) and 153 mg (170 μL; 1.53 mMol; I Eq.) ofN-methylpiperazine (Fluka 68810). After 2 h at rt, the yellow solutionis treated with 50 mL of NaHCO₃ satd. solution and extracted with ethylacetate. The combined organic layers are washed with water, dried(Na₂SO₄), filtered and concentrated under reduced pressure to approx. 10mL. The precipitated crystals are collected, washed with a little ethylacetate and dried at 60° C. under vacuum to obtain(4-{4-[3-(4-chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-ylamino}-phenyl)-(4methyl-piperazin-1-yl)-methanone.

Example 32{4-[3-(4-Chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-amine

To the suspension of 96 mg (2.53 mMol; 4 Eq.) of lithium aluminumhydride (Fluka 62420) in 20 mL of THF abs. under Argon at rt is addedslowly within 10 min 300 mg (0.633 mMol) of(4-{4-([3-(4-chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-ylamino}-phenyl)-(4-methyl-piperazin-1-yl)-methanone(see Example 31) as a solid; under vigorous foaming. After stirring for2.5 h at rt, the suspension is cooled to 0° C. and treated dropwise with20 mL of water. After diluting further with 50 mL of water, thesuspension is extracted with ethyl acetate. The combined organic layersare washed with water, dried (Na₂SO₄), filtered and concentrated underreduced pressure. The crude product is purified over silica gel, elutingwith CH₂Cl₂/CH₃OH (4:1) followed by trituration in diethyl ether toobtain{4-[3-(4-chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-amine.

Example 33{4-[3-(2,4-Dichloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-(3,4,5-trimethoxy-phenyl)-amine

{4-[3-(2,4-Dichloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-(3,4,5-trimethoxy-phenyl)-amineis synthesized from4-[3-(2,4-dichloro-phenyl)-1H-pyrazol-4-yl]-2-methanesulfonyl-pyrimidinein analogy to a literature procedure (Klutchko et al., Journal ofMedicinal Chemistry, 1998, Vol. 41, No. 17, 3276-3292) using3,4,5-trimethoxyaniline (Fluka 92129) and glacial HOAc.

Step 33.1: 2,4-Dichloro-N-methoxy-N-methyl-benzamide

The title compound is prepared in analogy to a standard protocol using2,4-dichloro-benzoyl chloride (Aldrich 11, 193-7) andN—O-dimethylhydroxylamine HCl (Fluka 40706) in CH₂Cl₂ (Nahm, Steven;Weinreb, Steven M.; Tetrahedron Lett.; 1981; 22 (39); 3815-3818).

Step 33.2:1-(2,4-Dichloro-phenyl)-2-(2-methylsulfanyl-pyrimidin-4-yl)-ethanone

To the solution of 85 mL of diisopropylamine (Fluka 38300) and 2.5 L ofTHF at −75° C. under Argon is added 370 mL (0.55 Mol) of butyl lithium(BuLi; 1.6N in hexanes; Fluka 20160) within 1 h. To this is added 71 g(0.5 Mol) of 4-methyl-2-methylsulfanyl-pyrimidine in 250 mL of CH₂Cl₂ at−75° C. within 30 min. After this, a solution of 118 g (0.5 Mol) of2,4dichloro-N-methoxy-N-methyl-benzamide in 250 mL of CH₂Cl₂ at −75° C.within 30 min followed by letting the mixture warn up to rt. Aftercompletion, the reaction mixture is poured onto 7 L of NH₄Cl satd. andextracted with ethyl acetate. The combined organic layers are washedwith brine, dried and evaporated. The crude product is suspended inhexanes. After filtering off and drying1-(2,4-dichloro-phenyl)-2-(2-methylsulfanyl-pyrimidin-4-yl)-ethanone isobtained as yellow crystals. Title compound: m.p.: 105-107° C.; ES-MS:313.0/314.9 [M+H]⁺.

4-Methyl-2-methylsulfanyl-pyrimidine is prepared from4-methyl-pyrimidine-2-thiol in analogy to a standard protocol usingmethyliodide (Strekowskl, L.; Wydra, R. L.; Janda, L.; Harden, D. B. J.Org. Chem. (1991), 56(19), 5610-14). Title compound: single peak at 3.94min (System 1); R_(f)=0.32 (ethyl acetate/hexane 1:2).

Step 33.3:4-[3-(2,4-Dichloro-phenyl)-1H-pyrazol-4-yl]-2-methylsulfanyl-pyrimidine

The title compound is prepared from1-(2,4-dichloro-phenyl)-2-(2-methylsulfanyl-pyrimidin-4-yl)-ethanone asdescribed in Example 1, Step 1.3, usingN,N-dimethylformamid-dimethylacetal and hydrazine monohydrate. Titlecompound: m.p.: 218-219° C.; single peak at 6.07 min (System 1).

Step 33.4:4-[3-(2,4-Dichloro-phenyl)-1H-pyrazol-4-yl]-2-methanesulfonyl-pyrimidine

The title compound is prepared from4-[3-(2,4-dichloro-phenyl)-1H-pyrazol-4-yl]-2-methylsulfanyl-pyrimidinein analogy to a literature procedure (Klutchko et al., Journal ofMedicinal Chemistry, 1998, Vol. 41, No. 17, 3276-3292) using m-CPBA(Fluka 25800) in CHCl₃. Title compound: ES-MS: 368.9 [M+H]⁺; single peakat t_(R)=4.98 min (System 1); R_(f)=0.38 (ethyl acetate).

Example 34{4-[3-(2,4-Dichloro-phenyl)-1H-pyrazol-4yl]-pyrimidin-2-yl}-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine

The title compound is prepared as described in Example 33 using4-(4-methyl-piperazin-1-yl)-phenylamine (see Example 1).

Example 35N(4-{4-[3-(4-Chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-N′,N′-dimethyl-benzene-1,3-diamine

The title compound is prepared as described in Example 1 using3-amino-N,N-dimethylaniline dihydrochloride (Fluka 07765).

Example 36{4-[3-(4-Ethoxy-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine

The title compound is prepared as described in Example 33 usingethyl-4-ethoxybenzoate 97% (ACROS 346590250) and4-(4-methyl-piperazin-1-yl)phenylamine (see Example 1).

Example 37{4-[3-(4-Ethoxy-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-(3,4,5-trimethoxy-phenyl)-amine

The title compound is prepared as described in Example 33 using4-ethoxy-benzoic acid ethyl ester (ACROS 346590250) and3,4,5-trimethoxyaniline (Fluka 92129).

Physicochemical Data:

melting point HPLC [min]/ mass spectra; ESI; Example from to System m/z= 1 282 284 3.45/1 444.3 [M − H]⁻ 2 236 239 3.48/1   435 [M + H]⁺ 3 191192 3.74/1   463 [M + H]⁺ 4 244 247 3.53/1   477 [M + H]⁺ 5 182 1833.46/1   435 [M + H]⁺ 6 192 193 3.54/1   477 [M + H]⁺ 7 179 181 3.74/1  463 [M + H]⁺ 8 297 299 3.43/1   446 [M + H]⁺ 9 273 277 3.15/1 442.0[M + H]⁺ 10 232 234 3.23/1 473.0 [M + H]⁺ 11 282 283 3.75/1 457.2 [M +H]⁺ 12 206 207 4.01/1 440.2 [M + H]⁺ 13 3.44/1 459.0 [M + H]⁺ 14 3.48/1459.3 [M + H]⁺ 15 3.28/1 473.2 [M + H]⁺ 16 3.17/1 442.2 [M + H]⁺ 17 242244 3.77/1 429.1 [M + H]⁺ 18 280 282 3.38/1 426.1 [M + H]⁺ 19 181 1823.68/1 440.2 [M + H]⁺ 20 206 207 3.41/1 415.1 [M + H]⁺ 21 188 191 3.73/1469.0 [M + H]⁺ 22 300 307 3.70/1 479.9 [M + H]⁺ 23 213 216 3.63/1 507.0[M + H]⁺ 24 305 309 2.40/1 428.1 [M + H]⁺ 25 289 294 3.43/1 426.0 [M +H]⁺ 26 251 259 3.45/1 415.1 [M + H]⁺ 27 225 228 4.15/1 475.0 [M + H]⁺ 28270 274 3.73/1 475.0 [M + H]⁺ 29 274 277 3.82/1 446.0 [M + H]⁺ 30 342349 4.53/1 391.9 [M + H]⁺ 31 173 175 3.63/1 473.9 [M + H]⁺ 32 240 2423.41/1 460.0 [M + H]⁺ 33 125 127 4.96/1 472.0 [M + H]⁺ 34 263 265 3.52/1477.9 [M + H]⁺ 35 3.90/1 391.2 [M + H]⁺ 36 3.37/1 456.2 [M + H]⁺ 37 293297 4.71/1

Sulfoxide-A and Sulfoxide-B can be prepared in analogy to thepreparation of the sulfone of Example 33 beginning with4-chloro-3-methoxy-benzoic acid and benzo[1,3]dioxole-5-carboxylic acid(Fluka), respectively, whereby the preparation of4-chloro3-methoxy-benzoic acid is known in the art (see also ‘Generalsynthetic scheme 3’).

Example 38{4-[3-(4-Chloro-3-methoxy-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-(3,4,5-trimethoxy-phenyl)-amine

Sulfoxide-A (100 mg, 0.28 mmoles) and the 3,4,5-trimethoxy aniline(524.9 mg, 2.86 mmoles) are dissolved in 1,4-dioxane (2 mL). Thereaction mixture is stirred at rt for 10 min, then BF₃.Et₂O (0.36 mL,2.86 mmoles) is added to above mixture dropwise at rt. The yellowsolution is stirred for 30 min at rt then heated to 100° C. overnight.After cooling to rt, the reaction is quenched with water. The aqueousphase is extracted with ethyl acetate. The combined organic phases aredried over sodium sulfate, concetrated and chromatographed on SiO₂(50-80% EtOAc/Hexanes) to afford the title compound as a light yellowsolid: ES-MS 468.1428 [M+H]; single peak at t_(R)=5.28 min (System 3);R_(f)=0.58 (100% EtOAc).

Example 393-{4-[3(4-Chloro-3-hydroxy-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-ylamino}-benzenesulfonamide

3-{4-[3-(4-Chloro-3-methoxy-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-ylamino}-benzenesulfonamide(Example 40) (94 mg, 0.2057 mmoles) is suspended in CH₂Cl₂ (20 mL) andcooled to −0° C. BBr₃ (0.5 mL, 1M in CH₂Cl₂) is added dropwise at −0° C.After 10 min the suspension is warmed to rt and kept at that temperatureovernight. The reaction is quenched with 1 mL of water and the reactionmixture is concentrated. The residue is chromatographed on SiO₂ (3%methanol/CH₂Cl₂) affording the title compound: ES-MS 443.1 [M+H]; singlepeak at t_(R)=4.318 min (System 3); R_(f)=0.53 (100% EtOAc).

Example 403-{4-[3-(4-Chloro-3-methoxy-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-ylamino}-benzenesulfonamide

Sulfoxide-A (200 mg, 0.572 mmoles) and 3-aminobenzenesulfonamide (680mg, 3.94 mmoles) are dissolved in 1,4dioxane (6 mL). The reactionmixture is stirred at rt for 5 min, then BF₃.Et₂O (0.72 mL, 5.76 mmoles)is added dropwise at rt. The reaction mixture is stirred 10 min at rt,then heated to 100° C. overnight. After cooling to rt the reaction isquenched with water and the aqueous phase is extracted with ethylacetate. The combined organic phases are dried over sodium sulfate,concentrated and chromatographed on SiO₂ (linear gradient 50→80% EtOAcin Hexanes) affording the title compound as a light yellow solid: ES-MS457.0869 [M+H]; single peak at t_(R)=4.930 min (System 3); R_(f)=0.58(100% EtOAc).

Example 413-{4-[3-(4-Chloro-3-methoxy-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-ylamino}-benzoicacid ethyl ester

Sulfoxide-A (50 mg, 0.143 mmoles) and 3-amino-benzoic acid ethyl ester(300 mg, 10.1 mmoles) are dissolved in 1,4-dioxane (2 mL). The reactionmixture is stirred at rt for 5 min, then BF₃.Et₂O (0.36 mL, 2.86 mmoles)is added to the reaction mixture dropwise at rt. The reaction mixture isstirred 10 min at rt then heated to 100° C. overnight. After cooling tort, the reaction mixture is diluted with water and a white solidprecipitated from solution. The solid is washed with methanol to givethe title compound: ES-MS 450.1350 [M+H]; single peak at t_(R)=6.10 min(System 3).

Example 423-{4-[3-(4-Chloro-3-hydroxy-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-ylamino}-benzoicacid ethyl ester

3-{4-[3-(4-Chloro-3-methoxy-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-ylamino}-benzoicacid ethyl ester (Example 41) (18 mg, 0.04 mmoles) is suspended inCH₂Cl₂ (2 mL) and cooled to −5° C. BBr₃ (0.5 mL, 1M in CH₂Cl₂) is addeddropwise at −5° C. After 10 min the suspension turns to a clear brownsolution. After 2 h at −5° C. another 0.5 mL of BBr₃ is added to thereaction mixture. Then the reaction mixture is warmed to rt and kept atthat temperature for 30 min. The reaction is quenched with 5 mL waterand stirred at rt overnight. The reaction mixture is extracted withethyl acetate. The combined organic phases are dried over sodiumsulfate, concentrated and chromatographed on SiO₂ (80% EtOAc/Hexanes)affording the title compound: ES-MS 436.1178 [M+H]; single peak att_(R)=5.579 min (System 3).

Example 431-(3-{4-[3-(4-Chloro-3-methoxy-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-ylamino}-phenyl)-ethanone

Sulfoxide-A (50 mg, 0.14 mmoles) and 1-(3-amino-phenyl)-ethanone (300mg, 2.22 mmoles) are dissolved in 1,4-dioxane (2 mL). The reactionmixture is stirred at rt for 5 min, then BF₃.Et₂O (0.36ml, 2.86 mmoles)is added to above mixture dropwise at rt. The reaction mixture isstirred 10 min at rt, then heated to 100° C. overnight. After cooling tort, the reaction mixture is diluted with CH₂Cl₂, then washed with water.The organic layer is separated and concentrated. The residue is washedwith CH₂Cl₂ and MeOH to afford the title compound as a solid: ES-MS420.1232 [M+H]; single peak at t_(R)=5.29 min (System 3); R_(f)=0.60(100% EtOAc).

Example 44Benzothiazol-6-yl-{4-[3-(4-chloro-3-methoxy-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-amine

Sulfoxide-A (100 mg, 0.286 mmoles) and benzothiazol-6-ylamine (430 mg,2.86 mmoles) are dissolved in 1,4-dioxane (2 mL). The reaction mixtureis stirred at rt for 10 min, then BF₃.Et₂O (0.36 mL, 2.86 mmoles) isadded dropwise at rt. The yellow solution is stirred 10 min at rt thenheated to 100° C. overnight. After cooling to rt, the reaction mixtureis quenched with water. The aqueous phase is extracted with ethylacetate. The combined organic phases are dried over sodium sulfate,concentrated and chromatographed on SiO₂ (linear gradient 50→80% EtOAcin Hexanes) to obtain the title compound as a light yellow product ES-MS435.0773 [M+H]; single peak at t_(R)=5.14 min (System 3); R_(f)=0.50(100% EtOAc).

Example 45{4-[3-(4-Chloro-3-methoxy-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-(1-oxo-benzothiazol-6-yl)-amine

A solution of OXONE (=KHSO₅; 141.4 mg, 0.23 mmoles) in water (2 mL) isadded dropwise to a suspension ofbenzothiazol-6-yl-{4-[3-(4-chloro-3-methoxy-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-amine(Example 44) (20 mg, 0.046 mmoles) in methanol (2 mL) at rt. Afterstirring overnight at rt the suspension is diluted with water upon whichthe suspension turns to a clear yellow solution. The reaction mixture isextracted with ethyl acetate. The combined organic phases are dried oversodium sulfate, concentrated and chromatographed on SiO₂ (5%MeOH/CH₂Cl₂) to yield the title compound as light yellow solid: ES-MS451.0751 [M+H]; single peak at t_(R)=4.93 min (System 3).

Example 46[4-(3-Benzo[1,3]dioxol-5-yl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-(3,4,5-trimethoxy-phenyl)-amine

Sulfoxide-B (50 mg, 0.1 522 mmoles) and 3,4,5-trimethoxy aniline (278.8mg, 1.522 mmoles) are dissolved in 1,4-dioxane (2 mL). The reactionmixture is stirred at rt for 10 min, then BF₃.Et₂O (0.19 mL, 1.522mmoles) is added dropwise at rt. The reaction mixture is stirred 10 minat rt, then heated to 100° C. overnight. After cooling to rt thereaction is quenched with water. The aqueous phase is extracted Withethyl acetate. The combined organic phases are dried over sodiumsulfate, concetrated and chromatographed on SiO₂ (linear gradient 50→80%EtOAc in Hexanes) affording the title compound as a light yellow solid:ES-MS 448.1608 [M+H]; single peak at t_(R)=4.579 min (System 3);R_(f)=0.58 (100% EtOAc).

Example 473-[4-(3-Benzo[1,3]dioxol-5-yl-1H-pyrazol-4-yl)pyrimidin-2-ylamino]-benzoicacid tert-butyl ester

Sulfoxide-B (206.6 mg, 0.63 mmol) and t-butyl-3-amino benzoate (370.5mg, 1.92 mmol) are dissolved in THF (30 mL). The reaction mixture isstirred at rt and BF₃.etherate (0.2 mL, 1.58 mmol) is added. After 4days at 80-100° C. more BF₃.etherate (0.1 mL, 0.79 mmol) is added. Thereaction mixture is heated for 1 h at 100° C., cooled to rt, and pouredover saturated NaCl (aq.). The crude product is extracted with EtOAc andthe combined organic layers are dried over MgSO₄, filtered,concentrated, chromatographed on SiO₂ (0.5-5% MeOH/CH₂Cl₂), andrecrystallized (THF/Hexane) to yield the title compound as an off-whitesolid: TOF-MS 458.1791 (M+H⁺); single peak at t_(R)=17.077 min (System5); R_(f)=0.5 (10% MeOH, 1% NH₄OH in CH₂Cl₂).

Example 48 3-[4-(3-Benzo[1,3]dioxol-5-yl-1H-pyrazol-4-yl)-pyrimidin-2-ylamino]-benzenesulfonamide

To Sulfoxide-B (378 mg, 1.15 mmol) and 3-amino-benzenesulfonamide (992mg, 5.76 mmol) in 1,4-dioxane is added BF₃.etherate (364 μL, 2.88 mmol).The reaction mixture is refluxed for 16 h at 100° C., cooled to rt, andconcentrated under reduced pressure. The residue is mixed with a minimumamount of water and extracted with EtOAc. The combined extracts aredried over MgSO₄, filtered, and concentrated. The residue ischromatographed on SiO₂ (2-5% MeOH/CH₂Cl₂) to yield an orange solid. Theorange solid is dissolved in MeOH and a precipitate is formed uponstanding. The mixture is filtered to give the title compound as a beigesolid: ES-MS 437 (M+H⁺); single peak at t_(R)=17.8 min (System 4);R_(f)=0.2 (1:20, MeOH/CH₂Cl₂, followed by 1:10, MeOH/CH₂Cl₂).

Example 49[4-(3-Benzo[1,3]dioxol-5-yl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-3-methylsulfanyl-phenyl)-amine

n-Butyl lithium (1.6 M in hexane, 2.28 mL, 3.65 mmol) is dropwise addedto 3-(methylthio)aniline (0.58 mL, 3.69 mmol) in THF (anhydrous, 10 mL)at −78° C. and stirred for 1 h. Sulfoxide-B (404.2 mg, 1.23 mmol) in THF(anhydrous, 20 mL) is added. The reaction mixture is allowed to warm tort, stirred for 41 h, and quenched with H₂O. The crude product isextracted with EtOAc. The organic layer is washed with saturated NaCl(aq.), dried over MgSO₄, filtered, concentrated, and chromatographed onSiO₂ (linear gradient 50→60% EtOAc in Hexane) to obtain the titlecompound as an off-white solid: ES-MS 404.3 (M+H)⁺; single peak att_(R)=16.264 min (System 5); R_(f)=0.17 (50% EtOAc/Hexane).

Example 50{4-[3-(2,3-Dimethyl-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(4-methyl-piperazin-1-yl)phenyl]-amine

The title compound is prepared as described in Example 33 using2,3-dimethyl-benzoic acid ethyl ester.

2,3Dimethylbenzoic acid ethyl ester is prepared from 2,3-dimethylbenzoicacid (98% Lancaster) as described in Example 5.

Example 51{4-[3-(2,3-Dimethyl-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-(3,4,5-trimethoxy-phenyl)-amine

The title compound is prepared as described in Example 33 using2,3-dimethyl-benzoic acid ethyl ester (see Example 50) and3,4,5-trimethoxyphenylamine.

Example 52{4-[3-(2-Chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine

The title compound is prepared as described in Example 33 using ethyl2-chlorobenzoate (98% Lancaster).

Example 53{4-[3-(2-Chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-(3,4,5-trimethoxy-phenyl)-amine

The title compound is prepared as described in Example 33 using ethyl2chlorobenzoate (98% Lancaster) and 3,4,5-trimethoxyphenylamine.

Example 54{4-[1-(2-Dimethylamino-ethyl)-5-p-tolyl-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine

To the suspension of 90 mg (0.211 mMol) of[4-(4-methyl-piperazin-1-yl)-phenyl]-[4-(3-p-tolyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine(Example 25) in 4.5 mL of THF is added 38 mg (0.426 mMol) of2-dimethylamino-ethanol (Fluka) and 122 mg (0.465 mMol) oftriphenylphosphine (Fluka). The yellowish suspension is cooled to 0° C.and treated with 81 mg (0.465 mMol) of DEAD*. The mixture is stirredwithout cooling for 17 h, followed by heating for 24 h at 60° C. Aftercooling to rt, the reaction mixture is filtered and washed with 5 mL ofTHF. The filtrate is concentrated under reduced pressure and the crudeproduct is purified by repeated chromatography on silica gel, elutingwith CH₂Cl₂/MeOH (9:1) and CH₂Cl₂/MeOH/H₂O 70:30:5 to obtain the titlecompound as beige crystals.

* Literature: Mitsunobu, Oyo; Synthesis 1981, p. 1-27.

Example 55{4-[1-(2-Dimethylamino-ethyl)-3-p-tolyl-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine

The title compound is prepared as described in Example 54 and isolatedfrom the same reaction mixture.

Example 56{4-[5-(2,4-Dichloro-phenyl)-1-methyl-1H-pyrazol-4-yl]-pyrimidin-2-yl}-(3,4-dimethoxy-phenyl)-amine

The title compound is prepared as described in Example 1 but using2-chloro[5-(2,4-dichloro-phenyl)-1-methyl-1H-pyrazol-4-yl]-pyrimidineand 3,4-dimethoxy-phenylamine.

2-Chloro-4-[5-(2,4dichloro-phenyl)-1-methyl-1H-pyrazol-4-yl]-pyrimidine:

To the solution of 1 g (3.07 mMol) of2-chloro-4-[3-(2,4-dichloro-phenyl)-1H-pyrazol-4-yl]-pyrimidine in 10 mLof DMF is added 0.467 g (3.38 mMol) of potassium carbonate at rt underan atmosphere of Argon. After stirring for 30 min, 1.15 mL (18.42 mMol)of methyl iodide is added. After completion of the reaction (28 h), themixture is poured onto 100 mL of water, and extracted repeatedly withethyl acetate. The combined organic layers are washed with NaHCO₃,water, brine, dried (Na₂SO₄), filtered and concentrated under reducedpressure. The crude product is purified twice over silica gel, elutingwith ethyl acetate/hexanes (1:1) and CH₂Cl₂/MeOH (99:1) to obtain thetitle compound as orange crystals; m.p. 122-125° C.; TLC (silica gel)R_(f)=0.19 (CH₂Cl₂/MeOH 99:1).

2-Chloro-4-[3-(2,4-dichloro-phenyl)-1H-pyrazol-4-yl]-pyrimidine isprepared as described in Example 1 using 2,4-dichloro-benzoic acid ethylester m.p. 83-90° C.; TLC (silica gel) R_(f)=0.28 (ethyl acetate/hexane1:1).

Example 57{4-[3-(2,4Dichloro-phenyl)-1-methyl-1H-pyrazol-4-yl]-pyrimidin-2-yl}-(3,4-dimethoxy-phenyl)-amine

The title compound is prepared as described in Example 1 but using2-chloro-4-[3-(2,4-dichloro-phenyl)-1-methyl-1H-pyrazol-4-yl]-pyrimidineand 3,4-dimethoxy-phenylamine.

2-Chloro-4-[3-(2,4-dichloro-phenyl)-1-methyl-1H-pyrazol-4-yl]pyrimidine:

The title compound is prepared as described in Example 56 for2-chloro[5-(2,4-dichloro-phenyl)-1-methyl-1H-pyrazol-4-yl]-pyrimidineand isolated from the same reaction mixture as yellow-orange crystals;m.p. 165-166° C.; TLC (silica gel) R_(f) 0.38 (CH₂Cl₂/MeOH 99:1).

Example 58 4-[4-(3-p-Tolyl-1H-pyrazol-4-yl)-pyrimidin-2-ylamino]-benzoicacid

The title compound is prepared as described in Example 30 using4-methyl-benzoic acid ethyl ester.

Example 59(4Methyl-piperazin-1-yl)-{4-[4-(3-p-tolyl-1H-pyrazol-4-yl)-pyrimidin-2-ylamino]-phenyl}-methanone

The title compound is prepared as described in Example 31 using4-[4(3-p-tolyl-1H-pyrazol-4-yl)-pyrimidin-2-ylamino]-benzoic acid(Example 58).

Example 60[4-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-[4-(3-p-tolyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine

The title compound is prepared as described in Example 32 using(4-methyl-piperazin-1-yl)-{4-[4-(3-p-tolyl-1H-pyrazol-4-yl)-pyrimidin-2-ylamino]-phenyl}-methanone(Example 59).

Example 61{4-[3-(4-Chloro-phenyl)-1-(2-dimethylamino-ethyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl-}4-[4-(4-methyl-piperazin-1-yl)-phenyl]1-amine

The title compound is prepared as described in Example 55 using4-chloro-benzoic acid ethyl ester.

Example 62{4-[5-(4-Chloro-phenyl)-1-(2-dimethylamino-ethyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-4-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine

The title compound is prepared as described in Example 54 using4-chloro-benzoic acid ethyl ester.

Example 63[4-(4-Methyl-piperazin-1-yl)-phenyl]-[4-(1-methyl-5-p-tolyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine

The title compound is prepared as described in Example 54 using methanolinstead.

Example 64[4-(4-Methyl-piperazin-1-yl)-phenyl]-[4-(1-methyl-3-p-tolyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine

The title compound is prepared as described in Example 55 usingmethanol.

Example 65[4-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-[4(1-methyl-5-p-tolyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine

The title compound is prepared as described in Example 54 starting from[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-[4-(3-p-tolyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine(Example 60) and methanol.

Example 66[4-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-[4-(1-methyl-3-p-tolyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine

The title compound is prepared as described in Example 55 starting from[4(4methyl-piperazin-1-ylmethyl)-phenyl]-[4-(3-p-tolyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine(Example 60) and methanol.

Example 67{4-[3-(4-Chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-(3,4,5-trimethoxy-phenyl)-amine

The title compound is prepared as described in Example 1 using3,4,5-trimethoxyphenylamine.

Example 68{4-[3-(4-Chloro-phenyl)-1H-pyrazol-4yl]-pyrimidin-2-yl}-(3,4-dimethoxy-phenyl)-amine

The title compound is prepared as described in Example 1 using3,4dimethoxy-phenylamine.

Example 69{4-[3-(4-Chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-(3-methoxy-phenyl)-amine

The title compound is prepared as described in Example 1 using4methoxy-phenylamine.

Example 70{4-[3-(4-Chloro-phenyl)-1-(2-dimethylamino-ethyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-(3,4,5-trimethoxy-phenyl)-amine

The title compound is prepared as described in Example 55 starting from{4-[3-(4-chloro-phenyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}-(3,4,5-trimethoxy-phenyl)-amine(Example 67).

Example 71{4-[5-(4-Chloro-phenyl)-1-(2-dimethylamino-ethyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-(3,4,5-trimethoxy-phenyl)-amine

The title compound is prepared as described in Example 54 starting from{4-[3-(4-chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-(3,4,5-trimethoxy-phenyl)-amine(Example 67).

Example 72{4-[5-(4-Chloro-phenyl)-1-(2-dimethylamino-ethyl)-1H-pyrazol-4yl]-pyrimidin-2-yl}-(3,4,5-trimethoxy-phenyl)-amine

The title compound is prepared as described in Example 55 starting from{4-[3-(4-chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-(3,4-dimethoxy-phenyl)-amine(Example 68).

Example 73{4-[5-(4-Chloro-phenyl)-1-(2-dimethylamino-ethyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-(3,4-dimethoxy-phenyl)-amine

The title compound is prepared as described in Example 54, starting from{4-[3-(4-chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-(3,4-dimethoxy-phenyl)-amine(Example 68).

Example 74{4-[3-(4Chloro-phenyl)-1-(2-dimethylamino-ethyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-(3-methoxy-phenyl)-amine

The title compound is prepared as described in Example 55 starting from{4-[3-(4chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-(3-methoxy-phenyl)-amine(Example 69).

Example 75{-4-[5-(4Chloro-phenyl)-1-(2-dimethylamino-ethyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-(3-methoxy-phenyl)-amine

The title compound is prepared as described in Example 54 starting from{4-[3-(4-chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-(3-methoxy-phenyl)-amine(Example 69).

Example 76{4-[3-(4-Chloro-phenyl)-1-(2-dimethylamino-ethyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-amine

The title compound is prepared as described in Example 55, starting from{4-[3-(4-chloro-phenyl)1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(4-methyl-piperazin-1-yl-methyl)-phenyl]-amine(Example 32) and 2-dimethylamino-ethanol (Fluka).

Example 77{4-[5-(4-Chloro-phenyl)-1-(2-dimethylamino-ethyl)-1H-pyrazol-4yl]-pyrimidin-2-yl}-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-amine

The title compound is prepared as described in Example 54, starting from{4-[3-(4-chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(4-methyl-piperazin-1-yl-methyl)-phenyl]-amine(Example 32) and 2-dimethylamino-ethanol (Fluka).

Example 78{4-[3-(4-Chloro-phenyl)-1-methyl-1H-pyrazol-4yl]-pyrimidin-2-yl}-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-amine

The title compound is prepared as described in Example 55 starting from{4-[3-(4chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(4-methyl-piperazin-1-yl-methyl-phenyl]-amine(Example 32) and methanol.

Example 79{4-[5-(4Chloro-phenyl)-1-methyl-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-amine

The title compound is prepared as described in Example 54 starting from{4-[3-(4-chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl)}-[4-(4-methyl-piperazin-1-yl-methyl)-phenyl]-amine(Example 32) and methanol.

Example 80{4-[3-(4-Chloro-phenyl)-1-(1-methyl-piperidin-4-yl)-1H-pyrazol-4yl]-pyrimidin-2-yl}-[4-(4-methyl-piperazin-1-yl-methyl)-phenyl]-amine

The title compound is prepared as described in Example 55 starting from{4-[3-(4chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(4-methyl-piperazin-1-yl-methyl)-phenyl]-amine(Example 32) and 1-methyl-piperidin-4-ol.

Example 81{4-[5-(4-Chloro-phenyl)-1-(1-methyl-piperidin-4yl)-1H-pyrazol-4yl]-pyrimidin-2-yl}-[4-(4methyl-piperazin-1-ylmethyl)-phenyl]-amine

The title compound is prepared as described in Example 54 starting from{4-[3-(4-chloro-phenyl)-1H-pyrazol-4yl]-pyrimidin-2-yl}-[4-(4-methyl-piperazin-1-yl-methyl)-phenyl]-amine(Example 32) and 1-methyl-piperidin-4-ol.

Example 82{4-[1-(2-Dimethylamino-ethyl)-5-p-tolyl-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(4methyl-piperazin-1-ylmethyl)-phenyl]-amine

The title compound is prepared as described in Example 54 starting from[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-[4-3-p-tolyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine(Example 60) and 2-dimethylamino-ethanol.

Example 83{4-[1-(2-Dimethylamino-ethyl)-3-p-tolyl-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-amine

The title compound is prepared as described in Example 55 starting from[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-[4-(3-p-tolyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine(Example 60) and 2-dimethylamino-ethanol.

Example 84[4-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-{4-[1-(1-methyl-piperidin-4-yl)-5-p-tolyl-1H-pyrazol-4-yl]-pyrimidin-2-yl}-amine

The title compound is prepared as described in Example 54 starting from[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-[4-(3-p-tolyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine(Example 60 and 1-methyl-piperidin-4-ol.

Example 85[4-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-{4-[1-(1-methyl-piperidin-4-yl)-3-p-tolyl-1H-pyrazol-4-yl]-pyrimidin-2-yl}-amine

The title compound is prepared as described in Example 55 starting from[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-[4-(3-p-tolyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine(Example 60) and 1-methyl-piperidin-4-ol.

Physical Characterization: data Examples 50-85 Example HPLC [min.]/ massspectra; No. m.p. from to [° C.] System 1 ESI; m/z = [M + H]⁺ 50 305 3073.48 51 249 250 4.78 52 310 315 3.18 53   257.5 259.5 4.43 54 184 1872.60 55 174 176 2.86 56 157 159 5.04 57 180 182 5.01 58 341 355 4.16 59264 266 3.29 60 250 253 3.17 61 148 156 2.93 62 173 179 2.64 63 261 2633.65 64 203 206 3.52 65 192 193 3.6 66 151 153 3.47 67 271 277 4.67 68261 265 4.28 69 261 264 4.98 70 150 153 4.15 71 153 160 3.86 72amorphous 3.81 479.1 73 157 160 3.54 74 amorphous 4.45 449 75 118 1254.20 76 amorphous 2.90 531.2 77 159 163 2.68 78 166 169 3.51 79 186 1893.59 80 164 166 2.94 81 180 182 2.86 82 123 147 2.68 83  62 66 2.88 84187 188 2.80 85 174 175 2.93

Example 86{4-[3-(4-Chloro-3-methyl-phenyl)-1H-pyrazol-4yl]-pyrimidin-2-yl}-(3,4-dimethoxy-phenyl)-amine

The title compound is prepared as described in Example 1 using4-chloro-3-methyl-benzoic acid ethyl ester and 3,4-dimethoxy-phenylamineinstead.

Example 87(3-Methoxy-phenyl)-{4-[3-(4trifluoromethyl-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-amine

The title compound is prepared as described in Example 1 using4-trifluoromethyl-benzoic acid ethyl ester and 3-methoxy-phenylamineinstead.

Example 88(3-Methoxy-phenyl)-{4-[1-methyl-3-(4-trifluoromethyl-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-amine

The title compound is prepared as described in Example 55 starting from(3-methoxy-phenyl)-{4-[3-(4-trifluoromethyl-phenyl)-1H-pyrazol-4yl]-pyrimidin-2-yl}-amine(Example 87) and using methanol instead.

Example 89(3-Methoxy-phenyl)-{4-[1-methyl-5-(4-trifluoromethyl-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-amine

The title compound is prepared as described in Example 88 and isolatedfrom the same reaction mixture.

Example 90{4-[1-(2-Dimethylamino-ethyl)-3-(4-trifluoromethyl-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-(3-methoxy-phenyl)-amine

The title compound is prepared as described in Example 55 starting from(3-methoxy-phenyl)-{4-[3-(4-trifluoromethyl-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-amine(Example 87).

Example 91{4-[3-(4-Chloro-phenyl)1-methyl-1H-pyrazol-4yl]-pyrimidin-2-yl}-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine

The title compound is prepared as described in Example 55 starting from{4-[3-(4-chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine(Example 1) and using methanol instead.

Example 92{4-[5-(4-Chloro-phenyl)-1-methyl-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(4methyl-piperazin-1-yl)-phenyl]-amine

The title compound is prepared as described in Example 91 and isolatedfrom the same reaction mixture.

Example 93[4-(4-Methyl-piperazin-1-yl)-phenyl]-{4-[3-(4trifluoromethyl-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-amine

The title compound is prepared as described in Example 1 using4-trifluoromethyl-benzoic acid ethyl ester instead.

Example 94[4-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-{4-[3-(4-trifluoromethyl-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-amine

The title compound is prepared as described in Examples 30-32 using4-trifluoromethyl-benzoic acid ethyl ester instead.

Example 95[4-(3-p-Tolyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-(3-trifluoromethoxy-phenyl)-amine

The title compound is prepared as described in Example 1 using4-methyl-benzoic acid ethyl ester and 3-trifluoromethoxy-phenylamineinstead.

Example 96(4-Methanesulfonyl-phenyl)-[4-(3-p-tolyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine

The title compound is prepared as described in Example 1 using4-methyl-benzoic acid ethyl ester and 4-methyl-benzoic acid ethyl esterinstead.

Example 97(3-{4-[3-(4-Chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-ylamino}-phenyl)-(4-methyl-piperazin-1-yl)-methanone

The title compound is prepared as described in Examples 30-31 using3-amino-benzoic acid instead.

Example 98{4-[3-(4Chloro-phenyl)-1H-pyrazol-4yl]-pyrimidin-2-yl}-(4-methane-sulfonyl-phenyl)-amine

The title compound is prepared as described in Example 96 using4-chloro-benzoic acid ethyl ester instead.

Example 99{(3-Methoxy-phenyl)-[4-(3-p-tolyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine

The title compound is prepared as described in Example 1 using4-methyl-benzoic acid ethyl ester and 3-methoxy-phenylamine instead.

Example 100(3-Methoxy-phenyl)-{4-[3-(3-trifluoromethyl-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-amine

The title compound is prepared as described in Example 1 using3-trifluoromethyl-benzoic acid ethyl ester and 3-methoxy-phenylamineinstead.

Example 101[4-(4-Ethyl-piperazin-1-ylmethyl)-phenyl]-[4-(3-p-tolyl-1H-pyrazol-4)-pyrimidin-2-yl]-amine

The title compound is prepared as described in Examples 58-60 using1-ethyl-piperazine instead.

Example 102[3-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-[4-(3-p-tolyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine

The title compound is prepared as described in Examples 58-60 using3-amino-benzoic acid instead.

Example 103{4-[3-(4-Chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-amine

The title compound is prepared as described in Examples 58-60 using4-chloro-benzoic acid ethyl ester and 3-amino-benzoic acid instead.

Example 104[3-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-[4-(3-phenyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine

The title compound is prepared as described in Example 103.De-chlorination took place due to prolonged exposure to lithium aluminumhydride.

Example 105{4-[3-(4-Chloro-phenyl)-1-methyl-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-amine

The title compound is prepared as described in Example 88 starting from{4-[3-(4-chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[3(4-methyl-piperazin-1-yl-methyl)-phenyl]-amineExample 103).

Example 106{4-[5-(4-Chloro-phenyl)-1-methyl-1-H-pyrazol-4yl]-pyrimidin-2-yl}-[3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-amine

The title compound is prepared as described in Example 105 and isolatedfrom the same reaction mixture.

Physical Characterization: data Examples 86-106 Example m.p. from HPLC[min.]/ mass spectra; No. to [° C.] System 1 ESI; m/z = [M + H]⁺ 86 4.54422.1 87 260 275 5.34 88 173 174 5.96 89 167 168 5.81 90 111 115 4.72 91202 204 3.56 92 264 267 3.64 93 276 280 3.60 94 228 235 3.56 95 283 2846.25 96 305 307 4.59 97 338 343 3.47 98 293 296 4.76 99 266 273 4.83 100208 220 5.29 101 257 259 3.21 102 239 241 3.21 103 243 248 3.31 104 245248 2.92 105 152 157 3.64 106 125 130 3.71

Example 107{4-[3-(4-Chloro-phenyl)-1-(1methyl-piperidin-4-ylmethyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-(3-methoxy-phenyl)-amine

The title compound is prepared as described in Example 55 using3-methoxy-phenylamine and 1-methyl-4-piperidinemethanol (Chem Pacific;33077; for preparation see also Example 27).

Example 108{4-[5-(4-Chloro-phenyl)-1-(1-methyl-piperidin-4-ylmethyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-(3-methoxy-phenyl)-amine

The title compound is prepared as described in Example 107 and isolatedfrom the same reaction mixture.

Example 109[4-(4-Ethyl-piperazin-1-yl)-phenyl]-[4-(3-p-tolyl-1H-pyrazol-4yl)-pyrimidin-2-yl]-amine

The title compound is prepared as described in Example 1 using4-methyl-benzoic acid ethyl ester and4-(4-ethyl-piperazin-1-yl)-phenylamine instead.

4-(4-Ethyl-piperazin-1-yl)-phenylamine is prepared in 2 steps from1-bromo-4-nitro-benzene and 1-ethyl-piperazine as described in Example1, Step A and B.

Example 110[4-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-{4-[3-(3-trifluoromethyl-phenyl)-1H-pyrazol-4yl]-pyrimidin-2-yl}-amine

The title compound is prepared as described in Examples 30-32 using3-trifluoromethyl-benzoic acid ethyl ester instead.

Example 1112-(4-{4-[4-(3-p-Tolyl-1H-pyrazol-4yl)-pyrimidin-2-ylamino]-benzyl}piperazin-1-yl)-ethanol

The title compound is prepared as described in Examples 58-60 using2-piperazin-1-yl-ethanol instead.

Example 112{4-[3-(4-Chloro-phenyl)-1-methyl-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[3-(1-methyl-piperidin-4-ylmethoxy)-phenyl]-amine

The title compound is prepared as described in Example 91 using3-(1-methyl-piperidin-4-ylmethoxy)-phenylamine instead.

For the preparation of 3-(1-methyl-piperidin-4-ylmethoxy)-phenylaminesee Example 125.

Example 1133-{4-[3-(3,5-Dimethoxy-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-ylamino}-benzenesulfonamide

The title compound is prepared as described in Example 1 using3,5-dimethoxy-benzoic acid ethyl ester and 3-amino-benzenesulfonamide.

Example 114{4-[3-(4-Chloro-phenyl)-1H-pyrazol-4yl]-pyrimidin-2-yl}-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-amine

The title compound is prepared as described in Example 32 using1-ethyl-piperazine instead.

Example 115[4-(4-Ethyl-piperazin-1-ylmethyl)-phenyl]-[4-(3-phenyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine

The title compound is prepared as described in Example 114.De-chlorination took place due to prolonged exposure to lithium aluminumhydride.

Example 116{4-[3-(4-Chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(1H-tetrazol-5-yl)-phenyl]-amine

The title compound is prepared starting from4-{4-[3-(4-chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-ylamino}-benzonitrile.4-{4-[3-(4-chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-ylamino}-benzonitrile(0.932 g; 2.5 mMol) is suspended in o-xylene (10 mL) and treated at rtwith azidotributyltin (1.66 g; 1.37 mL; 5 mMol). After stirring theyellow suspension at 160° C. for 117 h the reaction mixture is filteredoff without cooling and the crystals are washed with o-xylene. Since thereaction is still incomplete, the crude product is resuspended ino-xylene (20 mL) and treated at rt with azidotributyltin (1.37 mL; 5mMol). After stirring the yellow suspension at 160° C. for 117 h thereaction mixture is filtered off without cooling and the crystals arewashed with o-xylene. The crude product is suspended in methanol (1.00mL), refluxed and filtered without cooling. The crude product isacidified with 4N HCL/methanol and extracted with ethyl acetate. Theaqueous layer is basified with 4N NaOH (ca. pH 12) and extracted withethyl acetate. Upon this treatment, the product precipitates from theaqueous layer and is filtered off to obtain the title compound.

4-{4[3-(4-Chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-ylamino}-benzonitrile:

The title compound is prepared as described in Example 1 using4-aminobenzonitrile HCl salt instead.

Example 117[4-(4-Ethyl-piperazin-1-ylmethyl)-phenyl]-[4-(1-methyl-3-p-tolyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine

[4-(4-Ethyl-piperazin-1-ylmethyl)-phenyl]-[4-(3-p-tolyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine(Example 101) (165 mg; 0.364 mMol) is suspendend in toluene (3 mL) andtreated with DMF-DMA (168 mg; 1.32 mMol, 187 μL) at rt. The mixture isstirred at reflux for a total of 102 h whereby additional DMF-DMA isadded after 48 h (187 μL), after 61 h (187 μL) and after 82 h (374 μL).Upon completion of the reaction and cooling to rt the solvent is removedunder reduced pressure. The crude product mixture is purified byreversed phase chromatography (Lichroprep® RP18 15-25 μM; eluting with18% CH₃CN (0.1% TFA)/82% H₂O (0.1% TFA)). The pure fractions 27-34 arecombined and evaporated. The residue is dissolved in H₂O (2 mL) andneutralized with 1N NaOH. The crystalline product (free base) isfiltered off, washed with H₂O and dried at 60° C. to obtain the titlecompound as beige crystalline powder.

Example 118[4-(4-Ethyl-piperazin-1-ylmethyl)-phenyl]-[4-(1-methyl-5-p-tolyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine

The title compound is isolated from the reaction described in Example117. The pure fractions 40-59 are combined and evaporated. The residueis dissolved in H₂O (2 mL) and neutralized with 1N NaOH. The crystallineproduct (free base) is filtered off, washed with H₂O and dried at 60° C.to obtain the title compound as beige crystalline powder.

Example 119{4-[3-(4-Chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-{4-[(2,2,6,6-tetramethyl-piperidin-4-ylamino)-methyl]-phenyl}-amine

The title compound is prepared as described in Example 32 using2,2,6,6tetramethyl-piperidin-4-ylamine instead.

Example 120[4(3-Phenyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-{4[(2,2,6,6-tetramethyl-piperidin-4-ylamino)-methyl]-phenyl}-amine

The title compound is prepared as described in Example 119.De-chlorination took place due to prolonged exposure to lithium aluminumhydride.

Example 121{4-[3-(4-Chloro-phenyl)-1H-pyrazol-4yl]-pyrimidin-2-yl}-[4-(4-ethyl-piperazin-1-yl)-phenyl]-amine

The title compound is prepared as described in Example 109 using4-chloro-benzoic acid ethyl ester instead.

Example 122{4-[3-(4-Chloro-phenyl)-1H-pyrazol-4yl]-pyrimidin-2-yl}-(4piperazin-1-yl-phenyl)-amine

The title compound is prepared as described in Example 1 usingpiperazine instead.

Physical Characterization: data Examples 107-122 HPLC Example[min.]/System mass spectra; No. m.p. from to [° C.] [R1] ESI; m/z = [M +H]⁺ 107 65 68 4.44 108 180 182 4.21 109 280 282 3.27 110 221 223 3.45111 233 240 3.37 112 138 141 4.51 113 257 259 4.27 114 247 253 3.48 115227 233 3.14 116 369 372 4.42 117 88 90 3.72 118 82 85 3.86 119amorphous 3.60 516 120 213 220 3.25 121 268 271 3.58 122 214 226 3.38

Example 123[3-(1-Methyl-piperidin-4-yloxymethyl)-phenyl]-[4-(3-p-tolyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine

The title compound is prepared as described in Example 25 using3-(1-methyl-piperidin-4-yloxymethyl)-phenylamine.

3-(1-Methyl-piperidin-4-yloxymethyl)-phenylamine is prepared as follows:

A 500 mL 4-necked flask with mechanical stirrer, N₂ inlet and refluxcondenser is charged with 9.3 g (37.2 mmol)1-methyl-4-(3-nitro-benzyloxy)-piperidine and 150 mL of acetic acid.Under efficient stirring 13.14 g (223 mmol) of iron powder is added andthe mixture heated in an oil bath. At around 90 to 100° C. an exothermicreaction starts. The heating is interrupted for about 15 min until theexothermic reaction ceases and then the mixture is re-immersed into theoil bath and heated for 1 h at 120° C. The mixture is transferred to around-bottomed flask and the solvent removed under reduced pressure. Theresidue is taken up in 1N HCl and washed with ethyl acetate (3×200 mL).The aqueous phase is treated with sodium carbonate until PH 9-10. Thevoluminous precipitate is removed by filtration through Celite and thesolid washed extensively with ethyl acetate. The aqueous filtrate andthe ethyl acetate washings are separated and the aqueous phase extractedwith ethyl acetate. The organic phase is washed with brine, dried withsodium sulfate and evaporated. According to the H-NMR the residue iscomposed of a 1:1 mixture of the desired aniline and the correspondingacetanilide. The mixture is therefore dissolved in 50 mL of ethanol andtreated with 50 mL of 2N NaOH. The resulting mixture is heated 20 hunder reflux. After cooling the ethanol is distilled off and theremaining aqueous phase extracted with dichloromethane (2×150 mL). Theorganic phases are washed with brine, dried with potassium carbonate andevaporated. 3-(1-Methyl-piperidin-4-yloxymethyl)-phenylamine is obtainedas a brown viscous oil and used without further purification. HPLC: 7.54(System X2); [M+H]⁺221.0.

1-Methyl-4-(3-nitro-benzyloxy)-piperidine is prepared as follows:

4-Hydroxy-1-methylpiperidine (11.5 g, 0.1 mol) is dissolved in 250 mLdichloromethane. A solution of 100 g NaOH in 100 mL of water is addedfollowed by 17.2 g (0.1 mol) 3-nitro-benzylchloride and a catalyticamount of benzyl-triethylammonium chloride. The mixture is stirred veryefficiently during 2 h at rt and then poured into 300 mL of ice-coldwater. The organic layer is separated and the organic phase extractedonce more with dichloromethane. The organic phase is extracted with 1NHCl (2×200 mL) and the aqueous extracts adjusted to pH 9-10 by theaddition of solid sodium carbonate. The basic solution is extracted withethyl acetate (2×200 mL) and the organic phase washed with brine, driedover potassium carbonate and evaporated.1-Methyl-4-(3-nitro-benzyloxy)-piperidine is obtained as brown viscousoil. HPLC: 1.35 (System XS); [M+H]⁺ 251.0.

Example 124[3-(1-Methyl-piperidin-4-ylmethoxy)-phenyl]-[4-(3-p-tolyl-1H-pyrazol-4yl)-pyrimidin-2-yl]-amine

The title compound is prepared as described in Example 1 usingethyl-4-methylbenzoate (see Example 25) and[3-(1-methyl-piperidin-4-ylmethoxy)-phenyl]-carbamic acid tert-butylester (see Example 27).

Example 125[3-(1-Methyl-piperidin-4ylmethoxy)-phenyl]-[4-(1-methyl-3-p-tolyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine

3-(1-Methyl-piperidin-4-ylmethoxy)-phenylamine dihydrochloride (206 mg,0.7 mmol) is suspended in 1.5 mL n-butanol and 1.5 mL dioxane.2-Chloro-4-(1-methyl-3-p-tolyl-1H-pyrazol-4-yl)-pyrimidine (100 mg, 0.35mmol) is added and the mixture heated under reflux for 15 h. The yellowsuspension is evaporated to dryness and the residue portioned between 8mL 20% potassium carbonate solution and 10 mL dichloromethane. Theorganic phase is dried with sodium sulfate and evaporated. The crudeproduct is purified by flash-chromatography on Silica Gel usingdichloromethane/methanol 100:1.25→100:5 and thendichloromethane/methanol/conc. ammonia 100:5:0.25→100:10:0.25. The titlecompound is obtained as a foam.

2-Chloro-4-(1-methyl-3-p-tolyl-1H-pyrazol-4-yl)-pyrimidine is preparedas follows:

2-Chloro-4-(3p-tolyl-1H-pyrazol-4-yl)-pyrimidine (see Example 25, 1.35g, 0.005 mol) is suspended in 20 mL of toluene and treated with 2.7 mL(0.019 mol) N,N-dimeylformamide-dimethylacetal. The reaction mixture isheated 1 h at 60° C. and then 16 h at 120° C. The clear yellow solutionis evaporated. The crystalline residue is triturated with 10 mL ofether. The crystalline material is collected by filtration, washed withether and dried. 2-Chloro-4-(3-p-tolyl-1H-pyrazol-4-yl)-pyrimidine isobtained as colorless crystals. m.p. 194-197° C.; HPLC: 7.54 (SystemX2); [M+H]⁺ 221.0.

3-(1-Methyl-piperidin-4-ylmethoxy)-phenylamine dihydrochloride isprepared as follows:

[3-(1-Methyl-piperidin-4-ylmethoxy)-phenyl]-carbamic acid tert-butylester (1.6 g, 0.005 mol) is dissolved in 10 mL of methanol and treatedwith 10 mL 6 N HCl. The solution is stirred at rt over night and thenheated for 4 h to 60° C. The solvent is removed under reduced pressureand the residue dried under vacuum to give a tan foam which is usedwithout further purification. HPLC: 8.20 (System X2); [M+H]⁺ 221.0.

Example 1264-[4-(3-p-Tolyl-1H-pyrazol-4-yl)-pyrimidin-2-ylamino]-benzenesulfonamide

The title compound is prepared as described in Example 1 usingethyl-4-methylbenzoate (see Example 25) and 4-amino-benzenesulfonamide.

Example melting point HPLC [min]/ mass spectra; ESI; No. from to Systemm/z = 123 201 203 1.50/XS 455.0[M + H]⁺ 124 207 208 1.54/XS 455.0[M +H]⁺ 125 Foam 1.65/XS 469.0[M + H]⁺ 126 245 249 8.82/X1 407.0[M + H]⁺

Example 127 Dry-Filled Capsules

5000 capsules, each comprising as active ingredient 0.25 g of one of thecompounds of formula I mentioned in the preceding Examples, are preparedas follows:

active ingredient 1250 g  talcum 180 g wheat starch 120 g magnesiumstearate  80 g lactose  20 g

Preparation process: The mentioned substances are pulverised and forcedthrough a sieve of 0.6 mm mesh size. 0.33 g portions of the mixture areintroduced into gelatin capsules using a capsule-filling machine.

Example 128 Soft Capsules

5000 soft gelatin capsules, each comprising as active ingredient 0.05 gof one of the compounds of formula I mentioned in the precedingExamples, are prepared as follows:

active ingredient 250 g PEG 400 1 litre Tween 80 1 litre

Preparation process: The active ingredient is pulverised and suspendedin PEG 400 (polyethylene glycol having an M_(r) of from approx. 380 toapprox. 420, Fluka, Switzerland) and Tween®80 (polyoxyethylene sorbitanmonolaurate, Atlas Chem. Ind. Inc., USA, supplied by Fluka, Switzerland)and ground in a wet pulveriser to a particle size of approx. from 1 to 3μm. 0.43 9 portions of the mixture are then introduced into soft gelatincapsules using a capsule-filling machine.

Example 129 Inhibition of the tyrosine kinase Activity of EGF-R (HER-1),ErbB-2 (HER-2) and VEGF Receptor (KDR)

The inhibition tests are carried out as described above. The IC₅₀ valuesfor some of the compounds of formula I are given below:

Compound from HER-1 HER-2 KDR Example No. IC₅₀ [μM] IC₅₀ [μM] IC₅₀ [μM]1 0.018 0.023 0.01 2 0.022 0.019 0.021 18 0.021 0.013 0.004 20 0.0270.015 0.006 21 0.029 0.016 0.015 46 0.028 0.006 0.003 60 0.02 0.044 0.0191 0.018 0.042 0.028 101 0.013 0.028 0.004 109 0.016 0.034 0.003 1160.009 <0.01 0.021 124 0.003 0.017 0.005

1. A compound of formula I

wherein m is from 1 to 3; R₁ is amino-sulfonyl; N,N-di-lower alkylamino;lower alkyl-piperazinyl; lower alkyl substituted by loweralkyl-piperazinyl; a radical R₄-lower alkyl-X—, wherein R₄ isN,N-di-lower alkylamino, morpholinyl or lower alkyl-piperidyl, and X is—S—or —O—; or a radical R₅—C(═O)—, wherein R₅ is lower alkyl, hydroxyl,lower alkoxy or lower alkyl-piperazinyl; wherein the R₁ substituents areselected independently of one another if m>1; R₂ is hydrogen; R₃ is aradical of the formula Ia

wherein n is 1 or 2; and Z is chloro, lower alkyl, hydroxy, loweralkoxy, or phenyl-lower alkoxy; wherein the Z substituents are selectedindependently of one another if n>1; and R₃′ is hydrogen; or a salt ofthe said compounds.
 2. A compound of formula I according to claim 1,wherein m is from 1 or 2; R₁ is amino-sulfonyl; N,N-di-lower alkylamino;lower alkyl-piperazinyl; lower alkyl substituted by loweralkyl-piperazinyl; or a radical R₅—C(═O)—, wherein R₅ is lower alkyl,hydroxyl, lower alkoxy or lower alkyl-piperazinyl; wherein the R₁substituents are selected independently of one another if m is 2; R₂ ishydrogen; R₃ is a radical of the formula Ia, wherein n is 1 or 2 and Zis chloro, lower alkyl, hydroxy, or lower alkoxy; wherein the Zsubstituents are selected independently of one another if n is 2; andR₃′ is hydrogen; or a salt thereof.
 3. A compound of formula I accordingto claim 1, selected from the group consisting of{4-[3-(2,3-dimethyl-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine;{4-[3-(2-chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine;4-[4-(3-p-tolyl-1H-pyrazol-4-yl)-pyrimidin-2-ylamino]-benzoic acid;(4-Methyl-piperazin-1-yl)-{4-[4-(3-p-tolyl-1H-pyrazol-4-yl)-pyrimidin-2-ylamino]-phenyl}-methanone;[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-[4-(3-p-tolyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine;(3-{4-[3-(4-chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-ylamino}-phenyl)-(4-methyl-piperazin-1-yl)-methanone;[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-[4-(3-p-tolyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine;[3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-[4-(3-p-tolyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine;{4-[3-(4-chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-amine;[4-(4-ethyl-piperazin-1-yl)-phenyl]-[4-(3-p-tolyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine;3-{4-[3-(3,5-dimethoxy-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-ylamino}-benzenesulfonamide;{4-[3-(4-chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-amine;{4-[3-(4-chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(4-ethyl-piperazin-1-yl)-phenyl]-amine;{4-[3-(4-chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-(4-piperazin-1-yl-phenyl)-amine;[3-(1-methyl-piperidin-4-ylmethoxy)-phenyl]-[4-(3-p-tolyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine;4-[4-(3-p-tolyl-1H-pyrazol-4-yl)-pyrimidin-2-ylamino]-benzenesulfonamideand pharmaceutically acceptable salts thereof.
 4. A compound of formulaI according to claim 1, selected from the group consisting of{4-[3-(4-chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine;{4-[3-(4-chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(2-dimethyl-amino-ethoxy)-phenyl]-amine;{4-[3-(4-chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(2-diethylamino-ethoxy)-phenyl]-amine;{4-[3-(4-chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-amine;{4-[3-(3-chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(2-dimethylamino-ethoxy)-phenyl]-amine;{4-[3-(3-chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-amine;{4-[3-(3-chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(2-diethylamino-ethoxy)-phenyl]-amine;{4-[3-(3-chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine;{4-[3-(4-methoxy-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine;{4-[3-(4-methoxy-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-amine;{4-[3-(4-ethyl-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine;[4-(2-diethylamino-ethoxy)-phenyl]-{4-[3-(4-ethyl-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-amine;[4-(2-diethylamino-ethoxy)-phenyl]-{4-[3-(4-methoxy-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-amine;[4-(2-diethylamino-ethoxy)-phenyl]-{4-[3-(3-methoxy-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-amine;{4-[3-(3-methoxy-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-amine;{4-[3-(3-methoxy-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine;[4-(2-dimethylamino-ethoxy)-phenyl]-{4-[3-(4-ethyl-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-amine;[4-(4-methyl-piperazin-1-yl)-phenyl]-[4-(3-m-tolyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine;[4-(2-diethylamino-ethoxy)-phenyl]-[4-(3-m-tolyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine;[4-(2-dimethylamino-ethoxy)-phenyl]-[4-(3-m-tolyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine;{4-[3-(3,4-dichloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(2-dimethylamino-ethoxy)-phenyl]-amine;{4-[3-(3,4-dichloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine;{4-[3-(4-benzyloxy-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(2-dimethylamino-ethoxy)-phenyl]-amine;4-(4-{2-[4-(4-methyl-piperazin-1-yl)-phenylamino]pyrimidin-4-yl}-1H-pyrazol-3-yl)-phenol;[4-(4-methyl-piperazin-1-yl)-phenyl]-[4-(3-p-tolyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine;[4-(2-dimethylamino-ethoxy)-phenyl]-[4-(3-p-tolyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine;{4-[3-(4-chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[3-(1-methyl-piperidin-4-ylmethoxy)-phenyl]-amine;{4-[3-(4-chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(1-methyl-piperidin-4-ylmethoxy)-phenyl]-amine;{4-[3-(4-chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[3-(4-methyl-piperazin-1-yl)-phenyl]-amine;4-{4-[3-(4-chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-ylamino}-benzoicacid;(4-{4-[3-(4-chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-ylamino}-phenyl)-(4-methyl-piperazin-1-yl)-methanone;{4-[3-(4-chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-amine,{4-[3-(2,4-dichloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine;N-{4-[3-(4-chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-N′,N′-dimethyl-benzene-1,3-diamine;{4-[3-(4-ethoxy-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine;3-{4-[3-(4-chloro-3-hydroxy-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-ylamino}-benzenesulfonamide;3-{4-[3-(4-chloro-3-methoxy-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-ylamino}-benzenesulfonamide;3-{4-[3-(4-chloro-3-methoxy-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-ylamino}-benzoicacid ethyl ester;3-{4-[3-(4-chloro-3-hydroxy-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-ylamino}-benzoicacid ethyl ester;1-(3-{4-[3-(4-chloro-3-methoxy-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-ylamino}-phenyl)-ethanone;benzothiazol-6-yl-{4-[3-(4-chloro-3-methoxy-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-amine;{4-[3-(4-chloro-3-methoxy-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-(1-oxo-benzothiazol-6-yl)-amine;3-[4-(3-benzo[1,3]dioxol-5-yl-1H-pyrazol-4-yl)-pyrimidin-2-ylamino]-benzoicacid tert-butyl ester;3-[4-(3-benzo[1,3]dioxol-5-yl-1H-pyrazol-4-yl)-pyrimidin-2-ylamino]-benzenesulfonamide;and pharmaceutically acceptable salts thereof.
 5. A pharmaceuticalcomposition comprising a compound of formula I or a pharmaceuticallyacceptable salt thereof according to claim 1, together with at least onepharmaceutically acceptable carrier.
 6. A process for the preparation ofa compound of formula I according to claim 1 or of a salt of such acompound, characterized in that a) a compound of formula II

 wherein Y is a leaving group such as halogen, —S(═O)—CH₃ or —S(O₂)—CH₃and R₂, R₃ and R₃′ have the meanings as defined for a compound offormula I according to claim 1, is reacted with a compound of formulaIII

 wherein m and R₁ have the meanings as defined for a compound of formulaI according to claim 1; b) in order to prepare a compound of formula I,wherein R₁ is a radical R₅—C(═O)— in which R₆ is mono- or di-substitutedamino or a heterocyclic radical that is bound to the carbonyl moiety viaa nitrogen ring atom, a compound of formula IV

 wherein R₂, R₃ and R₃′ have the meanings as defined for a compound offormula I according to claim 1, or a reactive carboxylic acid derivativethereof, is reacted with a mono- or di-substituted amine or aheterocyclic radical containing at least one nitrogen ring atom to whicha hydrogen is bound, respectively; or c) in order to prepare a compoundof formula I, wherein R₂ is unsubstituted or substituted lower alkyl ora heterocyclic radical, a compound of formula I, wherein R₂ is hydrogen,is reacted with a compound of the formula R₂—OH, wherein R₂ isunsubstituted or substituted lower alkyl or a heterocyclic radicalwherein the substituted lower alkyl or the heterocyclic radical isattached to the hydroxy group of R₂—OH via a carbon atom of the loweralkyl moiety or via a carbon ring atom of the heterocyclic radical,respectively;  whereby functional groups which are present in thestarting compounds of processes a) to c) and are not intended to takepart in the reaction, are present in protected form if necessary, andprotecting groups that are present are cleaved, whereby the saidstarting compounds may also exist in the form of salts provided that asalt-forming group is present and a reaction in salt form is possible; and, if so desired, a compound of formula I thus obtained is convertedinto another compound of formula I, a free compound of formula I isconverted into a salt, an obtained salt of a compound of formula I isconverted into the free compound or another salt, and/or a mixture ofisomeric compounds of formula I is separated into the individualisomers.